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In the treatment of uveal melanoma (UVM), histone deacetylase inhibitors (HDACi) have emerged as a promising epigenetic therapy. However, their clinical efficacy is hindered by the suboptimal pharmacokinetics and the strong self‐rescue of tumor cells. To overcome these limitations, reactive oxygen species (ROS)‐responsive nanoparticles (NPs) are designed that encapsulate HDACi MS‐275 and the glutamine metabolism inhibitor V‐9302. Upon reaching the tumor microenvironment, these NPs can disintegrate, thereby releasing MS‐275 to increase the level of ROS and V‐9302 to reduce the production of glutathione (GSH) related to self‐rescue. These synergistic effects lead to a lethal ROS storm and induce cell pyroptosis. When combined with programmed cell death protein 1 monoclonal antibodies (α‐PD‐1), these NPs facilitate immune cell infiltration, improving anti‐tumor immunity, converting "immune‐cold" tumors into "immune‐hot" tumors, and enhancing immune memory in mice. The findings present a nano‐delivery strategy for the co‐delivery of epigenetic therapeutics and metabolic inhibitors, which induces pyroptosis in tumors cells and improves the effectiveness of chemotherapy and immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, there is limited knowledge regarding the role of HDACs in HNSCC. Consequently, this review aims to summarize the existing research findings and explore the potential association between HDACs and HNSCC, offering fresh perspectives on therapeutic approaches targeting HDACs that could potentially enhance the efficacy of HNSCC treatment. Additionally, the Cancer Genome Atlas (TCGA) dataset, CPTAC, HPA, OmicShare, GeneMANIA and STRING databases are utilized to provide supplementary evidence on the differential expression of HDACs, their prognostic significance and predicting functions in HNSCC patients. Graphical Abstract

Parkinson's disease is a progressive neurodegenerative disorder, predominantly of the motor system. Although some genetic components and cellular mechanisms of Parkinson's have been identified, much is still unknown. In recent years, emerging evidence has indicated that non-DNA-sequence variation (in particular epigenetic mechanisms) is likely to play a crucial role in the development and progression of the disease. Here, we present an up-to-date overview of epigenetic processes including DNA methylation, DNA hydroxymethylation, histone modifications and non-coding RNAs implicated in the brain of those with Parkinson's disease. We will also discuss the limitations of current epigenetic research in Parkinson's disease, the advantages of simultaneously studying genetics and epigenetics, and putative novel epigenetic therapies. [ABSTRACT FROM AUTHOR]

Opinion statement: The internal tandem duplication (ITD) mutation of the FMS-like receptor tyrosine kinase 3 (FLT3-ITD) is the most common mutation observed in approximately 30% of acute myeloid leukemia (AML) patients. It represents poor prognosis due to continuous activation of downstream growth-promoting signaling pathways such as STAT5 and PI3K/AKT. Hence, FLT3 is considered an attractive druggable target; selective small FLT3 inhibitors (FLT3Is), such as midostaurin and quizartinib, have been clinically approved. However, patients possess generally poor remission rates and acquired resistance when FLT3I used alone. Various factors in patients could cause these adverse effects including altered epigenetic regulation, causing mainly abnormal gene expression patterns. Epigenetic modifications are required for hematopoietic stem cell (HSC) self-renewal and differentiation; however, critical driver mutations have been identified in genes controlling DNA methylation (such as DNMT3A, TET2, IDH1/2). These regulators cause leukemia pathogenesis and affect disease diagnosis and prognosis when they co-occur with FLT3-ITD mutation. Therefore, understanding the role of different epigenetic alterations in FLT3-ITD AML pathogenesis and how they modulate FLT3I's activity is important to rationalize combinational treatment approaches including FLT3Is and modulators of methylation regulators or pathways. Data from ongoing pre-clinical and clinical studies will further precisely define the potential use of epigenetic therapy together with FLT3Is especially after characterized patients' mutational status in terms of FLT3 and DNA methlome regulators. [ABSTRACT FROM AUTHOR]

DNA methyltransferase inhibitors (DNMTi) have demonstrated benefit in reversing resistance to systemic therapies for several cancer types. In a phase II trial of guadecitabine and irinotecan compared to regorafenib or TAS‐102 in pts with advanced mCRC refractory to irinotecan. Patients with mCRC refractory to irinotecan were randomized 2:1 to guadecitabine and irinotecan (Arm A) vs standard of care regorafenib or TAS‐102 (Arm B) on a 28‐day cycle. Between January 15, 2016 and October 24, 2018, 104 pts were randomized at four international sites, with 96 pts undergoing treatment, 62 in Arm A and 34 in Arm B. Median overall survival was 7.15 months for Arm A and 7.66 months for Arm B (HR 0.93, 95% CI: 0.58–1.47, P =.75). The Kaplan–Meier rates of progression free survival at 4 months were 32% in Arm A and 26% in Arm B. Common ≥Grade 3 treatment related adverse events in Arm A were neutropenia (42%), anemia (18%), diarrhea (11%), compared to Arm B pts with neutropenia (12%), anemia (12%). Guadecitabine and irinotecan had similar OS compared to standard of care TAS‐102 or regorafenib, with evidence of target modulation. Clinical trial information: NCT01896856. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults. Although primary UM can be effectively controlled, a significant proportion of cases (40% or more) eventually develop distant metastases, commonly in the liver. Metastatic UM remains a lethal disease with limited treatment options. The initiation of UM is typically attributed to activating mutations in GNAQ or GNA11. The elucidation of the downstream pathways such as PKC/MAPK, PI3K/AKT/mTOR, and Hippo‐YAP have provided potential therapeutic targets. Concurrent mutations in BRCA1 associated protein 1 (BAP1) or splicing factor 3b subunit 1 (SF3B1) are considered crucial for the acquisition of malignant potential. Furthermore, in preclinical studies, actionable targets associated with BAP1 loss or oncogenic mutant SF3B1 have been identified, offering promising avenues for UM treatment. This review aims to summarize the emerging targeted and epigenetic therapeutic strategies for metastatic UM carrying specific driver mutations and the potential of combining these approaches with immunotherapy, with particular focus on those in upcoming or ongoing clinical trials. [ABSTRACT FROM AUTHOR]

The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, there is limited knowledge regarding the role of HDACs in HNSCC. Consequently, this review aims to summarize the existing research findings and explore the potential association between HDACs and HNSCC, offering fresh perspectives on therapeutic approaches targeting HDACs that could potentially enhance the efficacy of HNSCC treatment. Additionally, the Cancer Genome Atlas (TCGA) dataset, CPTAC, HPA, OmicShare, GeneMANIA and STRING databases are utilized to provide supplementary evidence on the differential expression of HDACs, their prognostic significance and predicting functions in HNSCC patients. [ABSTRACT FROM AUTHOR]

Abstract In the treatment of uveal melanoma (UVM), histone deacetylase inhibitors (HDACi) have emerged as a promising epigenetic therapy. However, their clinical efficacy is hindered by the suboptimal pharmacokinetics and the strong self‐rescue of tumor cells. To overcome these limitations, reactive oxygen species (ROS)‐responsive nanoparticles (NPs) are designed that encapsulate HDACi MS‐275 and the glutamine metabolism inhibitor V‐9302. Upon reaching the tumor microenvironment, these NPs can disintegrate, thereby releasing MS‐275 to increase the level of ROS and V‐9302 to reduce the production of glutathione (GSH) related to self‐rescue. These synergistic effects lead to a lethal ROS storm and induce cell pyroptosis. When combined with programmed cell death protein 1 monoclonal antibodies (α‐PD‐1), these NPs facilitate immune cell infiltration, improving anti‐tumor immunity, converting “immune‐cold” tumors into “immune‐hot” tumors, and enhancing immune memory in mice. The findings present a nano‐delivery strategy for the co‐delivery of epigenetic therapeutics and metabolic inhibitors, which induces pyroptosis in tumors cells and improves the effectiveness of chemotherapy and immunotherapy.

Abstract Background Inhibition of cyclin-dependent kinase 9 (CDK9), a novel epigenetic target in cancer, can reactivate epigenetically silenced genes in cancer by dephosphorylating the SWI/SNF chromatin remodeler BRG1. Here, we characterized the anti-tumor efficacy of MC180295, a newly developed CDK9 inhibitor. Methods In this study, we explored the pharmacokinetics of MC180295 in mice and rats, and tested the anti-tumor efficacy of MC180295, and its enantiomers, in multiple cancer cell lines and mouse models. We also combined CDK9 inhibition with a DNA methyltransferase (DNMT) inhibitor, decitabine, in multiple mouse models, and tested MC180295 dependence on T cells. Drug toxicity was measured by checking body weights and complete blood counts. Results MC180295 had high specificity for CDK9 and high potency against multiple neoplastic cell lines (median IC50 of 171 nM in 46 cell lines representing 6 different malignancies), with the highest potency seen in AML cell lines derived from patients with MLL translocations. MC180295 is a racemic mixture of two enantiomers, MC180379 and MC180380, with MC180380 showing higher potency in a live-cell epigenetic assay. Both MC180295 and MC180380 showed efficacy in in vivo AML and colon cancer xenograft models, and significant synergy with decitabine in both cancer models. Lastly, we found that CDK9 inhibition-mediated anti-tumoral effects were partially dependent on CD8 + T cells in vivo, indicating a significant immune component to the response. Conclusions MC180380, an inhibitor of cyclin-dependent kinase 9 (CDK9), is an efficacious anti-cancer agent worth advancing further toward clinical use.

Breast cancer (BC) is the most common non-skin cancer and the second leading cause of cancer death in American women. The initiation and progression of BC can proceed through the accumulation of genetic and epigenetic changes that allow transformed cells to escape the normal cell cycle checkpoint control. Unlike nucleotide mutations, epigenetic changes such as DNA methylation, histone posttranslational modifications (PTMs), nucleosome remodeling and non-coding RNAs are generally reversible and therefore potentially responsive to pharmacological intervention. Epigenetic dysregulations are critical mechanisms for impaired antitumor immunity, evasion of immune surveillance, and resistance to immunotherapy. Compared to highly immunogenic tumor types, such as melanoma or lung cancer, breast cancer has been viewed as an immunologically quiescent tumor which displays a relatively low population of tumor-infiltrating lymphocytes (TIL), low tumor mutational burden (TMB) and modest response rates to immune checkpoint inhibitors (ICI). Emerging evidence suggests that agents targeting aberrant epigenetic modifiers may augment host antitumor immunity in BC via several interrelated mechanisms such as enhancing tumor antigen presentation, activation of cytotoxic T cells, inhibition of immunosuppressive cells, boosting response to ICI, and induction of immunogenic cell death (ICD). These discoveries have established a highly promising basis for using combinatorial approaches of epigenetic drugs with immunotherapy as an innovative paradigm to improve outcomes of BC patients. In this review, we summarize the current understanding of how epigenetic processes regulate immune cell function and antitumor immunogenicity in the context of the breast tumor microenvironment. Moreover, we discuss the therapeutic potential and latest clinical trials of the combination of immune checkpoint blockers with epigenetic agents in breast cancer. [ABSTRACT FROM AUTHOR]

Background: Inhibition of cyclin-dependent kinase 9 (CDK9), a novel epigenetic target in cancer, can reactivate epigenetically silenced genes in cancer by dephosphorylating the SWI/SNF chromatin remodeler BRG1. Here, we characterized the anti-tumor efficacy of MC180295, a newly developed CDK9 inhibitor. Methods: In this study, we explored the pharmacokinetics of MC180295 in mice and rats, and tested the anti-tumor efficacy of MC180295, and its enantiomers, in multiple cancer cell lines and mouse models. We also combined CDK9 inhibition with a DNA methyltransferase (DNMT) inhibitor, decitabine, in multiple mouse models, and tested MC180295 dependence on T cells. Drug toxicity was measured by checking body weights and complete blood counts. Results: MC180295 had high specificity for CDK9 and high potency against multiple neoplastic cell lines (median IC50 of 171 nM in 46 cell lines representing 6 different malignancies), with the highest potency seen in AML cell lines derived from patients with MLL translocations. MC180295 is a racemic mixture of two enantiomers, MC180379 and MC180380, with MC180380 showing higher potency in a live-cell epigenetic assay. Both MC180295 and MC180380 showed efficacy in in vivo AML and colon cancer xenograft models, and significant synergy with decitabine in both cancer models. Lastly, we found that CDK9 inhibition-mediated anti-tumoral effects were partially dependent on CD8 + T cells in vivo, indicating a significant immune component to the response. Conclusions: MC180380, an inhibitor of cyclin-dependent kinase 9 (CDK9), is an efficacious anti-cancer agent worth advancing further toward clinical use. [ABSTRACT FROM AUTHOR]

Breast cancer comprises a substantial proportion of cancer diagnoses in women and is a primary cause of cancer-related mortality. While hormone-responsive cases generally have a favorable prognosis, the aggressive nature of triple-negative breast cancer presents challenges, with intrinsic resistance to established treatments being a persistent issue. The complexity intensifies with the emergence of acquired resistance, further complicating the management of breast cancer. Epigenetic changes, encompassing DNA methylation, histone and RNA modifications, and non-coding RNAs, are acknowledged as crucial contributors to the heterogeneity of breast cancer. The unique epigenetic landscape harbored by each cellular component within the tumor microenvironment (TME) adds great diversity to the intricate regulations which influence therapeutic responses. The TME, a sophisticated ecosystem of cellular and non-cellular elements interacting with tumor cells, establishes an immunosuppressive microenvironment and fuels processes such as tumor growth, angiogenesis, and extracellular matrix remodeling. These factors contribute to challenging conditions in cancer treatment by fostering a hypoxic environment, inducing metabolic stress, and creating physical barriers to drug delivery. This article delves into the complex connections between breast cancer treatment response, underlying epigenetic changes, and vital interactions within the TME. To restore sensitivity to treatment, it emphasizes the need for combination therapies considering epigenetic changes specific to individual members of the TME. Recognizing the pivotal role of epigenetics in drug resistance and comprehending the specificities of breast TME is essential for devising more effective therapeutic strategies. The development of reliable biomarkers for patient stratification will facilitate tailored and precise treatment approaches.

Abstract Cancer immunotherapy using immune-checkpoint inhibitors (ICIs) has revolutionized the field of cancer treatment; however, ICI efficacy is constrained by progressive dysfunction of CD8+ tumor-infiltrating lymphocytes (TILs), which is termed T cell exhaustion. This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment (TIME). Simultaneously, tumorigenesis entails robust reshaping of the epigenetic landscape, potentially instigating T cell exhaustion. In this review, we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion, and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies. Finally, we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.

Abstract Background Rhabdomyosarcomas (RMS) are predominantly paediatric sarcomas thought to originate from muscle precursor cells due to impaired myogenic differentiation. Despite intensive treatment, 5-year survival for patients with advanced disease remains low (

Cancer immunotherapy using immune-checkpoint inhibitors (ICIs) has revolutionized the field of cancer treatment; however, ICI efficacy is constrained by progressive dysfunction of CD8+ tumor-infiltrating lymphocytes (TILs), which is termed T cell exhaustion. This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment (TIME). Simultaneously, tumorigenesis entails robust reshaping of the epigenetic landscape, potentially instigating T cell exhaustion. In this review, we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion, and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies. Finally, we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) are important components of the tumor microenvironment (TME), which drive the tumor immune escape by inducing immunosuppression. The expansion and function of MDSCs are tightly associated with signaling pathways induced by molecules from tumor cells, stromal cells, and activated immune cells in the TME. Although these pathways have been well-characterized, the understanding of the epigenetic regulators involved is incomplete. Since histone modifications are the most studied epigenetic changes in MDSCs, we summarize current knowledge on the role of histone modifications in MDSCs within this review. We first discuss the influence of the TME on histone modifications in MDSCs, with an emphasis on histone modifications and modifiers that direct MDSC differentiation and function. Furthermore, we highlight current epigenetic interventions that can reverse MDSC-induced immunosuppression by modulating histone modifications and discuss future research directions to fully appreciate the role of histone modifications in MDSCs. [Display omitted] • MDSCs induce immunosuppression and drive tumor immune escape in the TME. • Signaling pathways in the TME impact histone modifications that regulate MDSC differentiation and function. • Epigenetic interventions targeting histone modifications hold potential for reversing MDSC-induced immunosuppression. [ABSTRACT FROM AUTHOR]

Background: Rhabdomyosarcomas (RMS) are predominantly paediatric sarcomas thought to originate from muscle precursor cells due to impaired myogenic differentiation. Despite intensive treatment, 5-year survival for patients with advanced disease remains low (< 30%), highlighting a need for novel therapies to improve outcomes. Differentiation therapeutics are agents that induce differentiation of cancer cells from malignant to benign. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2) suppresses normal skeletal muscle differentiation and is highly expressed in RMS tumours. Results: We demonstrate combining inhibition of the epigenetic modulator EZH2 with the differentiating agent retinoic acid (RA) is more effective at reducing cell proliferation in RMS cell lines than single agents alone. In PAX3-FOXO1 positive RMS cells this is due to an RA-driven induction of the interferon pathway resulting in apoptosis. In fusion negative RMS, combination therapy led to an EZH2i-driven upregulation of myogenic signalling resulting in differentiation. In both subtypes, EZH2 is significantly associated with enrichment of trimethylated lysine 27 on histone 3 (H3K27me3) in genes that are downregulated in untreated RMS cells and upregulated with EZH2 inhibitor treatment. These results provide insight into the mechanism that drives the anti-cancer effect of the EZH2/RA single agent and combination treatment and indicate that the reduction of EZH2 activity combined with the induction of RA signalling represents a potential novel therapeutic strategy to treat both subtypes of RMS. Conclusions: The results of this study demonstrate the potential utility of combining EZH2 inhibitors with differentiation agents for the treatment of paediatric rhabdomyosarcomas. As EZH2 inhibitors are currently undergoing clinical trials for adult and paediatric solid tumours and retinoic acid differentiation agents are already in clinical use this presents a readily translatable potential therapeutic strategy. Moreover, as inhibition of EZH2 in the poor prognosis FPRMS subtype results in an inflammatory response, it is conceivable that this strategy may also synergise with immunotherapies for a more effective treatment in these patients. [ABSTRACT FROM AUTHOR]

FBXW8 plays an irreplaceable role in the substrate recognition of ubiquitin-dependent proteolysis, which further regulates cell cycle progression and signal transduction. However, the abnormal expression of FBXW8 triggers malignancy, inflammation, and autophagy irregulation. FBXW8 is considered as an effective therapeutic target for Cullin-RING ligase 7 (CRL7)-related cancers. Still, the lack of selective inhibitors hinders further therapeutic development and limits the exploration of its biological mechanism. This study constructed an integrated protocol that combines pharmacophore modeling, structure-based virtual screening, and Molecular Dynamic Simulation. It was then used as a screening query to identify hit compounds targeted at the substrate recognition site of FBXW8 from a large-scale compound database including 120 million compounds. Then, ten lead compounds were retrieved by using molecular docking analysis and ADMET prediction. Finally, MD simulations were performed to validate the binding stability of selected drug candidates. The result indicated that three newly obtained compounds, namely ZINC96179876, ZINC72174069, and ZINC97730272, might be potent FBXW8 inhibitors against CRL7-related cancers such as endometrial cancer. [ABSTRACT FROM AUTHOR]

Structural fetal diseases, such as congenital diaphragmatic hernia (CDH) can be diagnosed prenatally. Neonates with CDH are healthy in utero as gas exchange is managed by the placenta, but impaired lung function results in critical illness from the time a baby takes its first breath. MicroRNA (miR) 200b and its downstream targets in the TGF-β pathway are critically involved in lung branching morphogenesis. Here, we characterize the expression of miR200b and the TGF-β pathway at different gestational times using a rat model of CDH. Fetal rats with CDH are deficient in miR200b at gestational day 18. We demonstrate that novel polymeric nanoparticles loaded with miR200b, delivered in utero via vitelline vein injection to fetal rats with CDH results in changes in the TGF-β pathway as measured by qRT-PCR; these epigenetic changes improve lung size and lung morphology, and lead to favorable pulmonary vascular remodeling on histology. This is the first demonstration of in utero epigenetic therapy to improve lung growth and development in a pre-clinical model. With refinement, this technique could be applied to fetal cases of CDH or other forms of impaired lung development in a minimally invasive fashion.

Targeting aberrant epigenetic programs that drive tumorigenesis is a promising approach to cancer therapy. DNA-encoded library (DEL) screening is a core platform technology increasingly used to identify drugs that bind to protein targets. Here, we use DEL screening against bromodomain and extra-terminal motif (BET) proteins to identify inhibitors with new chemotypes, and successfully identified BBC1115 as a selective BET inhibitor. While BBC1115 does not structurally resemble OTX-015, a clinically active pan-BET inhibitor, our intensive biological characterization revealed that BBC1115 binds to BET proteins, including BRD4, and suppresses aberrant cell fate programs. Phenotypically, BBC1115-mediated BET inhibition impaired proliferation in acute myeloid leukemia, pancreatic, colorectal, and ovarian cancer cells in vitro. Moreover, intravenous administration of BBC1115 inhibited subcutaneous tumor xenograft growth with minimal toxicity and favorable pharmacokinetic properties in vivo. Since epigenetic regulations are ubiquitously distributed across normal and malignant cells, it will be critical to evaluate if BBC1115 affects normal cell function. Nonetheless, our study shows integrating DEL-based small-molecule compound screening and multi-step biological validation represents a reliable strategy to discover new chemotypes with selectivity, efficacy, and safety profiles for targeting proteins involved in epigenetic regulation in human malignancies.

Peripheral T cell lymphomas (PTCL) are a heterogenous group of mature T cell lymphomas with an overall poor prognosis. Understanding the molecular heterogeneity in PTCL subtypes may lead to improved understanding of the underlying biological mechanisms driving these diseases. Mutations in the epigenetic regulator TET2 are among the most frequent mutations identified in PTCL, with the highest frequency in angioimmunoblastic T cell lymphomas and other nodal T follicular helper (TFH) lymphomas. This review dissects the role of TET2 in nodal TFH cell lymphomas with a focus on emerging biological insights into the molecular mechanism promoting lymphomagenesis and the potential for epigenetic therapies to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

DNA methylation is the most important epigenetic element that activates the inhibition of gene transcription and is included in the pathogenesis of all types of malignancies. Remarkably, the effectors of DNA methylation are DNMTs (DNA methyltransferases) that catalyze de novo or keep methylation of hemimethylated DNA after the DNA replication process. DNA methylation structures in cancer are altered, with three procedures by which DNA methylation helps cancer development which are including direct mutagenesis, hypomethylation of the cancer genome, and also focal hypermethylation of the promoters of TSGs (tumor suppressor genes). Conspicuously, DNA methylation, nucleosome remodeling, RNA-mediated targeting, and histone modification balance modulate many biological activities that are essential and indispensable to the genesis of cancer and also can impact many epigenetic changes including DNA methylation and histone modifications as well as adjusting of non-coding miRNAs expression in prevention and treatment of many cancers. Epigenetics points to heritable modifications in gene expression that do not comprise alterations in the DNA sequence. The nucleosome is the basic unit of chromatin, consisting of 147 base pairs (bp) of DNA bound around a histone octamer comprised of one H3/H4 tetramer and two H2A/H2B dimers. DNA methylation is preferentially distributed over nucleosome regions and is less increased over flanking nucleosome-depleted DNA, implying a connection between nucleosome positioning and DNA methylation. In carcinogenesis, aberrations in the epigenome may also include in the progression of drug resistance. In this report, we report the rudimentary notes behind these epigenetic signaling pathways and emphasize the proofs recommending that their misregulation can conclude in cancer. These findings in conjunction with the promising preclinical and clinical consequences observed with epigenetic drugs against chromatin regulators, confirm the important role of epigenetics in cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Protocadherin 10 (PCDH 10), a member of the superfamily of protocadherins, is a Ca2+-dependent homophilic cell-cell adhesion molecule expressed on the surface of cell membranes. Protocadherin 10 plays a critical role in the central nervous system including in cell adhesion, formation and maintenance of neural circuits and synapses, regulation of actin assembly, cognitive function and tumor suppression. Additionally, Pcdh10 can serve as a non-invasive diagnostic and prognostic indicator for various cancers. Methods: This paper collects and reviews relevant literature in Pubmed. Conclusion: This review describes the latest research understanding the role of Pcdh10 in neurological disease and human cancer, highlighting the importance of scrutinizing its properties for the development of targeted therapies and identifying a need for further research to explore Pcdh10 functions in other pathways, cell types and human pathologies. [ABSTRACT FROM AUTHOR]

Abstract The tumor immune microenvironment represents a sophisticated ecosystem where various immune cell subtypes communicate with cancer cells and stromal cells. The dynamic cellular composition and functional characteristics of the immune landscape along the trajectory of cancer development greatly impact the therapeutic efficacy and clinical outcome in patients receiving systemic antitumor therapy. Mounting evidence has suggested that epigenetic mechanisms are the underpinning of many aspects of antitumor immunity and facilitate immune state transitions during differentiation, activation, inhibition, or dysfunction. Thus, targeting epigenetic modifiers to remodel the immune microenvironment holds great potential as an integral part of anticancer regimens. In this review, we summarize the epigenetic profiles and key epigenetic modifiers in individual immune cell types that define the functional coordinates of tumor permissive and non-permissive immune landscapes. We discuss the immunomodulatory roles of current and prospective epigenetic therapeutic agents, which may open new opportunities in enhancing cancer immunotherapy or overcoming existing therapeutic challenges in the management of cancer.

Peripheral T cell lymphomas (PTCL) are a heterogenous group of mature T cell lymphomas with an overall poor prognosis. Understanding the molecular heterogeneity in PTCL subtypes may lead to improved understanding of the underlying biological mechanisms driving these diseases. Mutations in the epigenetic regulator TET2 are among the most frequent mutations identified in PTCL, with the highest frequency in angioimmunoblastic T cell lymphomas and other nodal T follicular helper (TFH) lymphomas. This review dissects the role of TET2 in nodal TFH cell lymphomas with a focus on emerging biological insights into the molecular mechanism promoting lymphomagenesis and the potential for epigenetic therapies to improve clinical outcomes.

CD8+ T cell exhaustion is a stable dysfunctional state driven by chronic antigen stimulation in the tumor microenvironment (TME). Differentiation of exhausted CD8+ T cells (CD8+ TEXs) is accompanied by extensive transcriptional, epigenetic and metabolic reprogramming. CD8+ TEXs are mainly characterized by impaired proliferative and cytotoxic capacity as well as the increased expression of multiple co-inhibitory receptors. Preclinical tumor studies and clinical cohorts have demonstrated that T cell exhaustion is firmly associated with poor clinical outcomes in a variety of cancers. More importantly, CD8+ TEXs are regarded as the main responder to immune checkpoint blockade (ICB). However, to date, a large number of cancer patients have failed to achieve durable responses after ICB. Therefore, improving CD8+ TEXs may be a breakthrough point to reverse the current dilemma of cancer immunotherapy and eliminate cancers. Strategies to reinvigorate CD8+ TEXs in TME mainly include ICB, transcription factor-based therapy, epigenetic therapy, metabolism-based therapy and cytokine therapy, which target on different aspects of exhaustion progression. Each of them has its advantages and application scope. In this review, we mainly focus on the major advances of current strategies to reinvigorate CD8+ TEXs in TME. We summarize their efficacy and mechanisms, identify the promising monotherapy and combined therapy and propose suggestions to enhance the treatment efficacy to significantly boost anti-tumor immunity and achieve better clinical outcomes. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia（AML）is a malignant hematopoietic stem cell disease characterized by clonal expansion of abnormally differentiated myeloid blasts. It mainly occurs in the elderly, and the median age at diagnosis is 68 years old. The current treatment is intensive induction chemotherapy with or without allogeneic hematopoietic stem cell transplantation, but this method cannot be applied to elderly patients who account for more than 50% of AML patients. Epigenetic alterations play an important role in the pathogenesis of AML, and these epigenetic alterations have become targets for the development of new anti-AML drugs. This article reviews the research progress of DNA methylation and histone modification in epigenetics and the research achievements of drug therapy. [ABSTRACT FROM AUTHOR]

Substantial evidence has shown that tumors can emerge from a distinct, small population of cells known as cancer stem cells (CSCs), which have a vital role in the initiation, maintenance, metastasis, drug resistance, and relapse of cancer. Hence, it is critical to identify drugs that selectively target and eliminate CSCs to induce a long-lasting therapeutic response and better patient outcomes. Modulations in epigenetic regulation contribute to cancer progression as it is crucial for both stem cell biology and chemoresistance. Polycomb group (PcG) and trithorax group (TrxG) proteins are identified as the key modulators of cellular memory that direct whether a stem cell will self-renew or differentiate. The dynamic interaction of these two groups of proteins with opposing effects on gene expression has opened up new avenues for understanding their role in tumorigenesis. Therefore, it is essential to elucidate the underlying mechanisms of aberrant epigenetic modifications, without which designing drugs becomes implausible. The existing cancer treatments like radiotherapy and chemotherapy have major limitations owing to treatment failure and recurrence of cancer. However, the application of epigenetic therapy has shown promising therapeutic results in clinical trials with its ability to reverse the aberrant epigenetic modifications that result in cancer and chemotherapy resistance. Future research aimed at developing drugs that are target specific is necessary to prevent off-target effects. To overcome the limitations of the current epidrugs, novel approaches like CRISPR/Cas9-based epigenetic editing are emerging as new hopes for targeted therapy in cancer. This article gives an overview of the till-date understanding of the role of epigenetics in cancer stem cell biology and recent developments in epigenetic therapy. [ABSTRACT FROM AUTHOR]

Aberrant DNA hypermethylation at regulatory cis-elements of particular genes is seen in a plethora of pathological conditions including cardiovascular, neurological, immunological, gastrointestinal and renal diseases, as well as in cancer, diabetes and others. Thus, approaches for experimental and therapeutic DNA demethylation have a great potential to demonstrate mechanistic importance, and even causality of epigenetic alterations, and may open novel avenues to epigenetic cures. However, existing methods based on DNA methyltransferase inhibitors that elicit genome-wide demethylation are not suitable for treatment of diseases with specific epimutations and provide a limited experimental value. Therefore, gene-specific epigenetic editing is a critical approach for epigenetic re-activation of silenced genes. Site-specific demethylation can be achieved by utilizing sequence-dependent DNA-binding molecules such as zinc finger protein array (ZFA), transcription activator-like effector (TALE) and clustered regularly interspaced short palindromic repeat-associated dead Cas9 (CRISPR/dCas9). Synthetic proteins, where these DNA-binding domains are fused with the DNA demethylases such as ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG) enzymes, successfully induced or enhanced transcriptional responsiveness at targeted loci. However, a number of challenges, including the dependence on transgenesis for delivery of the fusion constructs, remain issues to be solved. In this review, we detail current and potential approaches to gene-specific DNA demethylation as a novel epigenetic editing-based therapeutic strategy. [ABSTRACT FROM AUTHOR]

Epigenetic therapy is an emerging field in the treatment of human cancer, including hematologic malignancies. This class of therapeutic agents approved by the US Food and Drug Administration for cancer treatment includes DNA hypomethylating agents, histone deacetylase inhibitors, IDH1/2 inhibitors, EZH2 inhibitors, and numerous preclinical targets/agents. Most studies measuring the biological effects of epigenetic therapy focus their attention on either their direct cytotoxic effects on malignant cells or their effects on modifying tumor cell antigen expression, exposing them to immune surveillance mechanisms. However, a growing body of evidence suggests that epigenetic therapy also has effects on the development and function of the immune system, including natural killer cells, which can alter their response to cancer cells. In this review, we summarize the body of literature studying the effects of different classes of epigenetic therapy on the development and/or function of natural killer cells. [ABSTRACT FROM AUTHOR]

Background: Infectious complications reflect a major challenge in the treatment of patients with acute myeloid leukemia (AML). Both induction chemotherapy and epigenetic treatment with hypomethylating agents (HMA) are associated with severe infections, while neutropenia represents a common risk factor. Here, 220 consecutive and newly diagnosed AML patients were analyzed with respect to infectious complications dependent on treatment intensity and antifungal prophylaxis applied to these patients. Patients and methods: We retrospectively analyzed 220 patients with newly diagnosed AML at a tertiary care hospital between August 2016 and December 2020. The median age of AML patients undergoing induction chemotherapy (n = 102) was 61 years (25–76 years). Patients receiving palliative AML treatment (n = 118) had a median age of 75 years (53–91 years). We assessed the occurrence of infectious complication including the classification of pulmonary invasive fungal disease (IFD) according to the EORTC/MSG criteria at diagnosis and until day 100 after initiation of AML treatment. Furthermore, admission to intensive care unit (ICU) and subsequent outcome was analyzed for both groups of AML patients, respectively. Results: AML patients subsequently allocated to palliative AML treatment have a significantly higher risk of pneumonia at diagnosis compared to patients undergoing induction chemotherapy (37.3% vs. 13.7%, P < 0.001) including a higher probability of atypical pneumonia (22.0% vs. 10.8%, P = 0.026). Furthermore, urinary tract infections are more frequent in the palliative subgroup at the time of AML diagnosis (5.1% vs. 0%, P = 0.021). Surprisingly, the incidence of pulmonary IFD is significantly lower after initiation of palliative AML treatment compared to the occurrence after induction chemotherapy (8.4% vs. 33.3%, P < 0.001) despite only few patients of the palliative treatment group received Aspergillus spp.-directed antifungal prophylaxis. The overall risk for infectious complications at AML diagnosis is significantly higher for palliative AML patients at diagnosis while patients undergoing induction chemotherapy have a significantly higher risk of infections after initiation of AML treatment. In addition, there is a strong correlation between the occurrence of pneumonia including atypical pneumonia and pulmonary IFD and the ECOG performance status at diagnosis in the palliative AML patient group. Analysis of intensive care unit (ICU) treatment (e.g. in case of sepsis or pneumonia) for both subgroups reveals a positive outcome in 10 of 15 patients (66.7%) with palliative AML treatment and in 15 of 18 patients (83.3%) receiving induction chemotherapy. Importantly, the presence of infections and the ECOG performance status at diagnosis significantly correlate with the overall survival (OS) of palliative AML patients (315 days w/o infection vs. 69 days with infection, P 0.0049 and 353 days for ECOG < 1 vs. 50 days for ECOG > 2, P < 0.001, respectively) in this intent-to-treat analysis. Conclusion: The risk and the pattern of infectious complications at diagnosis and after initiation of AML therapy depends on age, ECOG performance status and subsequent treatment intensity. A comprehensive diagnostic work-up for identification of pulmonary IFD is indispensable for effective treatment of pneumonia in AML patients. The presence of infectious complications at diagnosis contributes to an inferior outcome in elderly AML patients. [ABSTRACT FROM AUTHOR]

Epigenetics has long been recognized as a significant field in biology and is defined as the investigation of any alteration in gene expression patterns that is not attributed to changes in the DNA sequences. Epigenetic marks, including histone modifications, non-coding RNAs, and DNA methylation, play crucial roles in gene regulation. Numerous studies in humans have been carried out on single-nucleotide resolution of DNA methylation, the CpG island, new histone modifications, and genome-wide nucleosome positioning. These studies indicate that epigenetic mutations and aberrant placement of these epigenetic marks play a critical role in causing the disease. Consequently, significant development has occurred in biomedical research in identifying epigenetic mechanisms, their interactions, and changes in health and disease conditions. The purpose of this review article is to provide comprehensive information about the different types of diseases caused by alterations in epigenetic factors such as DNA methylation and histone acetylation or methylation. Recent studies reported that epigenetics could influence the evolution of human cancer via aberrant methylation of gene promoter regions, which is associated with reduced gene function. Furthermore, DNA methyltransferases (DNMTs) in the DNA methylation process as well as histone acetyltransferases (HATs)/histone deacetylases (HDACs) and histone methyltransferases (HMTs)/demethylases (HDMs) in histone modifications play important roles both in the catalysis and inhibition of target gene transcription and in many other DNA processes such as repair, replication, and recombination. Dysfunction in these enzymes leads to epigenetic disorders and, as a result, various diseases such as cancers and brain diseases. Consequently, the knowledge of how to modify aberrant DNA methylation as well as aberrant histone acetylation or methylation via inhibitors by using epigenetic drugs can be a suitable therapeutic approach for a number of diseases. Using the synergistic effects of DNA methylation and histone modification inhibitors, it is hoped that many epigenetic defects will be treated in the future. Numerous studies have demonstrated a link between epigenetic marks and their effects on brain and cancer diseases. Designing appropriate drugs could provide novel strategies for the management of these diseases in the near future. [ABSTRACT FROM AUTHOR]

Epigenetic research has the potential to improve our understanding of the pathogenesis of cancer, specifically non-small-cell lung cancer, and support our efforts to personalize the management of the disease. Epigenetic alterations are expected to have relevance for early detection, diagnosis, outcome prediction, and tumor response to therapy. Additionally, epi-drugs as therapeutic modalities may lead to the recovery of genes delaying tumor growth, thus increasing survival rates, and may be effective against tumors without druggable mutations. Epigenetic changes involve DNA methylation, histone modifications, and the activity of non-coding RNAs, causing gene expression changes and their mutual interactions. This systematic review, based on 110 studies, gives a comprehensive overview of new perspectives on diagnostic (28 studies) and prognostic (25 studies) epigenetic biomarkers, as well as epigenetic treatment options (57 studies) for non-small-cell lung cancer. This paper outlines the crosstalk between epigenetic and genetic factors as well as elucidates clinical contexts including epigenetic treatments, such as dietary supplements and food additives, which serve as anti-carcinogenic compounds and regulators of cellular epigenetics and which are used to reduce toxicity. Furthermore, a future-oriented exploration of epigenetic studies in NSCLC is presented. The findings suggest that additional studies are necessary to comprehend the mechanisms of epigenetic changes and investigate biomarkers, response rates, and tailored combinations of treatments. In the future, epigenetics could have the potential to become an integral part of diagnostics, prognostics, and personalized treatment in NSCLC. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is an ever-increasing, insidious disease which reduces the quality of life of millions of elderly people around the world. AMD is characterised by damage to the retinal pigment epithelium (RPE) in the macula region of the retina. The origins of this multi-factorial disease are complex and still not fully understood. Oxidative stress and mitochondrial imbalance in the RPE are believed to be important factors in the development of AMD. In this review, the regulation of the mitochondrial function and antioxidant stress response by non-coding RNAs (ncRNAs), newly emerged epigenetic factors, is discussed. These molecules include microRNAs, long non-coding RNAs, and circular non-coding RNAs. They act mainly as mRNA suppressors, controllers of other ncRNAs, or by interacting with proteins. We include here examples of these RNA molecules which affect various mitochondrial processes and antioxidant signaling of the cell. As a future prospect, the possibility to manipulate these ncRNAs to strengthen mitochondrial and antioxidant response functions is discussed. Non-coding RNAs could be used as potential diagnostic markers for AMD, and in the future, also as therapeutic targets, either by suppressing or increasing their expression. In addition to AMD, it is possible that non-coding RNAs could be regulators in other oxidative stress-related degenerative diseases. [ABSTRACT FROM AUTHOR]

The tumor immune microenvironment represents a sophisticated ecosystem where various immune cell subtypes communicate with cancer cells and stromal cells. The dynamic cellular composition and functional characteristics of the immune landscape along the trajectory of cancer development greatly impact the therapeutic efficacy and clinical outcome in patients receiving systemic antitumor therapy. Mounting evidence has suggested that epigenetic mechanisms are the underpinning of many aspects of antitumor immunity and facilitate immune state transitions during differentiation, activation, inhibition, or dysfunction. Thus, targeting epigenetic modifiers to remodel the immune microenvironment holds great potential as an integral part of anticancer regimens. In this review, we summarize the epigenetic profiles and key epigenetic modifiers in individual immune cell types that define the functional coordinates of tumor permissive and non-permissive immune landscapes. We discuss the immunomodulatory roles of current and prospective epigenetic therapeutic agents, which may open new opportunities in enhancing cancer immunotherapy or overcoming existing therapeutic challenges in the management of cancer. [ABSTRACT FROM AUTHOR]

CD8+ T cell exhaustion is a stable dysfunctional state driven by chronic antigen stimulation in the tumor microenvironment (TME). Differentiation of exhausted CD8+ T cells (CD8+ TEXs) is accompanied by extensive transcriptional, epigenetic and metabolic reprogramming. CD8+ TEXs are mainly characterized by impaired proliferative and cytotoxic capacity as well as the increased expression of multiple co-inhibitory receptors. Preclinical tumor studies and clinical cohorts have demonstrated that T cell exhaustion is firmly associated with poor clinical outcomes in a variety of cancers. More importantly, CD8+ TEXs are regarded as the main responder to immune checkpoint blockade (ICB). However, to date, a large number of cancer patients have failed to achieve durable responses after ICB. Therefore, improving CD8+ TEXs may be a breakthrough point to reverse the current dilemma of cancer immunotherapy and eliminate cancers. Strategies to reinvigorate CD8+ TEXs in TME mainly include ICB, transcription factor-based therapy, epigenetic therapy, metabolism-based therapy and cytokine therapy, which target on different aspects of exhaustion progression. Each of them has its advantages and application scope. In this review, we mainly focus on the major advances of current strategies to reinvigorate CD8+ TEXs in TME. We summarize their efficacy and mechanisms, identify the promising monotherapy and combined therapy and propose suggestions to enhance the treatment efficacy to significantly boost anti-tumor immunity and achieve better clinical outcomes.

There is a close connection between epigenetic regulation, cancer metabolism, and immunology. The combination of epigenetic therapy and immunotherapy provides a promising avenue for cancer management. As an epigenetic regulator of histone acetylation, panobinostat can induce histone acetylation and inhibit tumor cell proliferation, as well as regulate aerobic glycolysis and reprogram intratumoral immune cells. JQ1 is a BRD4 inhibitor that can suppress PD-L1 expression. Herein, we proposed a chemo-free, epigenetic-based combination therapy of panobinostat/JQ1 for metastatic colorectal cancer. A novel targeted binary-drug liposome was developed based on lactoferrin-mediated binding with the LRP-1 receptor. It was found that the tumor-targeted delivery was further enhanced by in situ formation of albumin corona. The lactoferrin modification and endogenous albumin adsorption contribute a dual-targeting effect on the receptors of both LRP-1 and SPARC that were overexpressed in tumor cells and immune cells (e.g., tumor-associated macrophages). The targeted liposomal therapy was effective to suppress the crosstalk between tumor metabolism and immune evasion via glycolysis inhibition and immune normalization. Consequently, lactic acid production was reduced and angiogenesis inhibited; TAM switched to an anti-tumor phenotype, and the anti-tumor function of the effector CD8+ T cells was reinforced. The strategy provides a potential method for remodeling the tumor immune microenvironment (TIME).

Epigenetic alterations are implicated in tumour immune evasion and immune checkpoint blockade (ICB) resistance. SET domain bifurcated histone methyltransferase 1 (SETDB1) is a histone lysine methyltransferase that catalyses histone H3K9 di- and tri-methylation on euchromatin, and growing evidence indicates that SETDB1 amplification and abnormal activation are significantly correlated with the unfavourable prognosis of multiple malignant tumours and contribute to tumourigenesis and progression, immune evasion and ICB resistance. The main underlying mechanism is H3K9me3 deposition by SETDB1 on tumour-suppressive genes, retrotransposons, and immune genes. SETDB1 targeting is a promising approach to cancer therapy, particularly immunotherapy, because of its regulatory effects on endogenous retroviruses. However, SETDB1- targeted therapy remains challenging due to potential side effects and the lack of antagonists with high selectivity and potency. Here, we review the role of SETDB1 in tumourigenesis and immune regulation and present the current challenges and future perspectives of SETDB1 targeted therapy. [ABSTRACT FROM AUTHOR]

Background: Of the only 20% of patients with resectable pancreatic ductal adenocarcinoma (rPDA), cancer recurs in 80% of cases. Epigenetic dysregulation is an early hallmark of cancer cells acquiring metastatic potential, and epigenetic modulators may reactivate tumor suppressor genes, delay recurrence, and sensitize PDA to future chemotherapy. Methods: This was a randomized phase II study (NCT01845805) of CC-486 (oral DNA methyltransferase inhibitor azacitidine) vs. observation (OBS) in rPDA patients harboring high-risk features (stage pN1-2, R1 margins, or elevated CA 19–9 level) with no evidence of disease following standard adjuvant therapy. Patients were randomized to oral CC-486 treatment (300 mg daily on days 1–21 on a 28-day cycle) or OBS for up to 12 cycles or until disease relapse/unacceptable toxicities. Following recurrence, records of next-line therapies, imaging, and survival were obtained. The primary endpoint was progression-free survival (PFS)—time from randomization to recurrence (imaging/biopsy confirmed or death). Secondary endpoints included OS and PFS and ORR and metastatic PFS with subsequent next-line systemic therapy in metastatic setting. Results: Forty-nine patients (24 in CC-486 arm, 25 in OBS arm) were randomized: median age 66 (range 36–81), 53% male, 73% node positive, 49% elevated CA 19–9, 20% R1 resection, 63% and 100% received perioperative concurrent chemoradiation and chemotherapy, respectively. Median time from surgery to randomization was 9.6 mo (range 2.9–36.8). For the CC-486 arm, median treatment duration was 5.6 mo (range 1.3 to 12.8) with 14 treatment-related grade 3 or 4 AEs among 5 patients (22%) resulting in dose-reduction. Four patients (17%) discontinued therapy due to AEs. With median follow-up of 20.3mo (IQR 12.8, 41.4), 38 (79%) of evaluable patients recurred (34 imaging-confirmed, 4 clinically). Median PFS in imagining-confirmed cases was 9.2 and 8.9mo (HR 0.94, 95% CI 0.46–1.87, p = 0.85) for CC-486 and OBS patients, respectively. Median OS (2-yr OS%) was 33.8 (50%) and 26.4 mo (61%) in CC-486 and OBS patients, respectively. (HR 0.98, 95% CI 0.46–2.05, p = 0.96). ORR with subsequent chemotherapy in the metastatic setting was minimal in both arms. Conclusions: Treatment with CC-486 following adjuvant therapy did not prolong time-to-relapse in patients with high-risk rPDA or improve disease response on 1st-line metastatic therapy. [ABSTRACT FROM AUTHOR]

Reprogramming M2-type, pro-tumoral tumor-associated macrophages (TAMs) into M1-type, anti-tumoral macrophages is a key strategy in cancer therapy. In this study, we exploited epigenetic therapy using the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) and the histone deacetylation inhibitor trichostatin A (TSA), to reprogram M2-type macrophages into an M1-like phenotype. Treatment of M2-type macrophages with the combination of 5-aza-dC and TSA decreased the levels of M2 macrophage cytokines while increasing those of M1 macrophage cytokines, as compared to the use of either therapy alone. Conditioned medium of M2 macrophages treated with the combination of 5-aza-dC and TSA sensitized the tumor cells to paclitaxel. Moreover, treatment with the combination inhibited tumor growth and improved anti-tumor immunity in the tumor microenvironment. Depletion of macrophages reduced the anti-tumor growth activity of the combination therapy. Profiling of miRNAs revealed that the expression of miR-7083-5p was remarkably upregulated in M2 macrophages, following treatment with 5-aza-dC and TSA. Transfection of miR-7083-5p reprogrammed the M2-type macrophages towards an M1-like phenotype, and adoptive transfer of M2 macrophages pre-treated with miR-7083-5p into mice inhibited tumor growth. miR-7083-5p inhibited the expression of colony-stimulating factor 2 receptor alpha and CD43 as candidate targets. These results show that epigenetic therapy upon treatment with the combination of 5-aza-dC and TSA skews M2-type TAMs towards the M1-like phenotype by upregulating miR-7083-5p, which contributes to the inhibition of tumor growth. [ABSTRACT FROM AUTHOR]

Genomic imprinting is an epigenetic phenomenon of monoallelic gene expression pattern depending on parental origin. In humans, congenital imprinting disruptions resulting from genetic or epigenetic mechanisms can cause a group of diseases known as genetic imprinting disorders (IDs). Genetic IDs involve several distinct syndromes sharing homologies in terms of genetic etiologies and phenotypic features. However, the molecular pathogenesis of genetic IDs is complex and remains largely uncharacterized, resulting in a lack of effective therapeutic approaches for patients. In this review, we begin with an overview of the genomic and epigenomic molecular basis of human genetic IDs. Notably, we address ethical aspects as a priority of employing emerging techniques for therapeutic applications in human IDs. With a particular focus, we delineate the current field of emerging therapeutics for genetic IDs. We briefly summarize novel symptomatic drugs and highlight the key milestones of new techniques and therapeutic programs as they stand today which can offer highly promising disease-modifying interventions for genetic IDs accompanied by various challenges. [ABSTRACT FROM AUTHOR]

Despite the dramatic advances in our understanding of the etiology of colorectal cancer (CRC) in recent decades, effective therapeutic strategies are still urgently needed. Oncogenic mutations in the Wnt/β‐Catenin pathway are hallmarks of CRC. Moreover, long non‐coding RNAs (lncRNAs) as molecular managers are involved in the initiation, progression, and metastasis of CRC. Therefore, it is important to further explore the interaction between lncRNAs and Wnt/β‐Catenin signaling pathway for targeted therapy of CRC. Natural phytochemicals have not toxicity and can target carcinogenesis‐related pathways. Growing evidences suggest that flavonoids are inversely associated with CRC risk. These bioactive compounds could target carcinogenesis pathways of CRC and reduced the side effects of anti‐cancer drugs. The review systematically summarized the progress of flavonoids targeting lncRNA/Wnt axis in the investigations of CRC, which will provide a promising therapeutic approach for CRC and develop nutrition‐oriented preventive strategies for CRC based on epigenetic mechanisms. In the field, more epidemiological and clinical trials are required in the future to verify feasibility of targeting lncRNA/Wnt axis by flavonoids in the therapy and prevention of CRC. [ABSTRACT FROM AUTHOR]

Decitabine (DAC), a DNA methyltransferase (DNMT) inhibitor, is tested in combination with conventional anticancer drugs as a treatment option for various solid tumors. Although epigenome modulation provides a promising avenue in treating resistant cancer types, more studies are required to evaluate its safety and ability to normalize the aberrant transcriptional profiles. As deoxycytidine kinase (DCK)-mediated phosphorylation is a rate-limiting step in DAC metabolic activation, we hypothesized that its intracellular overexpression could potentiate DAC's effect on cell methylome and thus increase its therapeutic efficacy. Therefore, two breast cancer cell lines, JIMT-1 and T-47D, differing in their molecular characteristics, were transfected with a DCK expression vector and exposed to low-dose DAC (approximately IC20). Although transfection resulted in a significant DCK expression increase, further enhanced by DAC exposure, no transfection- induced changes were found at the global DNA methylation level or in cell viability. In parallel, an integrative approach was applied to decipher DAC-induced, methylation-mediated, transcriptomic reprogramming. Besides large- scale hypomethylation, accompanied by up-regulation of gene expression across the entire genome, DAC also induced hypermethylation and down-regulation of numerous genes in both cell lines. Interestingly, TET1 and TET2 expression halved in JIMT-1 cells after DAC exposure, while DNMTs' changes were not significant. The protein digestion and absorption pathway, containing numerous collagen and solute carrier genes, ranking second among membrane transport proteins, was the top enriched pathway in both cell lines when hypomethylated and up-regulated genes were considered. Moreover, the calcium signaling pathway, playing a significant role in drug resistance, was among the top enriched in JIMT-1 cells. Although low-dose DAC demonstrated its ability to normalize the expression of tumor suppressors, several oncogenes were also up-regulated, a finding, that supports previously raised concerns regarding its broad reprogramming potential. Importantly, our research provides evidence about the involvement of active demethylation in DAC-mediated transcriptional reprogramming. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment for patients with myeloid malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, relapse and graft-versus-host disease (GvHD) still affect the survival of patients who receive allo-HSCT, and more appropriate therapeutic strategies should be applied at all stages of transplantation to prevent these adverse events. The use of epigenetics agents, such as hypomethylating agents (HMAs), has been explored to decrease the risk of relapse by epigenetic modulation, which is especially effective among AML patients with poor mutations in epigenetic regulators. Furthermore, epigenetic agents have also been regarded as prophylactic methods for GvHD management without abrogating graft versus leukemia (GvL) effects. Therefore, the combination of epigenetic therapy and HSCT may optimize the transplantation process and prevent treatment failure. Existing studies have investigated the feasibility and effectiveness of using HMAs in the pretransplant, transplant and posttransplant stages among MDS and AML patients. This review examines the application of HMAs as a bridge treatment to reduce the tumor burden and the determine appropriate dose during allo-HSCT. Within this review, we also examine the efficacy and safety of HMAs alone or HMA-based strategies in posttransplant settings for MDS and AML. Finally, we provide an overview of other epigenetic candidates, which have been discussed in the nontransplant setting. [ABSTRACT FROM AUTHOR]

Simple Summary: We performed targeted sequencing to identify somatic mutations at the hairless (HR) gene locus in human breast tumors. We found HR mutations in approximately 15% of the patient cohort (n = 85), compared with 23% for BRCA2, 13% for GATA3, 7% for BRCA1, and 3% for PTEN in the same breast cancer patient cohort. We also found an average 23% HR copy number loss in breast cancers. HR reconstitution in HR-deficient human breast cancer cells significantly suppressed tumor growth in orthotopic xenograft mouse models. We further demonstrated that HR's antitumor activity was at least partly mediated by transcriptional activation of CELF2, a tumor suppressor with RNA-binding activity. Finally, we showed that pharmacologic inhibition of histone methylation is effective in suppressing HR-deficient breast tumor growth and progression. These findings suggest that HR loss plays an important role in breast cancer pathogenesis and will lead to future studies to explore specific inhibitors of HR-dependent histone methylation pathway to abrogate HR-deficient tumor growth and progression. The hairless (HR) gene encodes a transcription factor with histone demethylase activity that is essential for development and tissue homeostasis. Previous studies suggest that mutational inactivation of HR promotes tumorigenesis. To investigate HR mutations in breast cancer, we performed targeted next-generation sequencing using DNA isolated from primary breast cancer tissues. We identified HR somatic mutations in approximately 15% of the patient cohort (n = 85), compared with 23% for BRCA2, 13% for GATA3, 7% for BRCA1, and 3% for PTEN in the same patient cohort. We also found an average 23% HR copy number loss in breast cancers. In support of HR's antitumor functions, HR reconstitution in HR-deficient human breast cancer cells significantly suppressed tumor growth in orthotopic xenograft mouse models. We further demonstrated that HR's antitumor activity was at least partly mediated by transcriptional activation of CELF2, a tumor suppressor with RNA-binding activity. Consistent with HR's histone demethylase activity, pharmacologic inhibition of histone methylation suppressed HR-deficient breast cancer cell proliferation, migration and tumor growth. Taken together, we identified HR as a novel tumor suppressor that is frequently mutated in breast cancer. We also showed that pharmacologic inhibition of histone methylation is effective in suppressing HR-deficient breast tumor growth and progression. [ABSTRACT FROM AUTHOR]