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Abnormalities in epigenetic modifications can cause malignant transformations in cells, leading to cancers of the gastrointestinal (GI) tract, which accounts for 20% of all cancers worldwide. Among the epigenetic alterations, DNA hypomethylation is associated with genomic instability. In addition, CpG methylation and promoter hypermethylation have been recognized as biomarkers for different malignancies. In GI cancers, epigenetic alterations affect genes responsible for cell cycle control, DNA repair, apoptosis, and tumorigenic-specific signaling pathways. Understanding the pattern of alterations in DNA methylation in GI cancers could help scientists discover new molecular-based pharmaceutical treatments. This study highlights alterations in DNA methylation in GI cancers. Understanding epigenetic differences among GI cancers may improve targeted therapies and lead to the discovery of new diagnostic biomarkers., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

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.

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., (© 2024. The Author(s).)

Prostate cancer is one of the most common malignancies among men worldwide. Besides genetic alterations, epigenetic modulations including DNA methylation, histone modifications and miRNA mediated alteration of gene expression are the key driving forces for the prostate tumor development and cancer progression. Aberrant expression and/or the activity of the epigenetic modifiers/enzymes, results in aberrant expression of genes involved in DNA repair, cell cycle regulation, cell adhesion, apoptosis, autophagy, tumor suppression and hormone response and thereby disease progression. Altered epigenome is associated with prostate cancer recurrence, progression, aggressiveness and transition from androgen-dependent to androgen-independent phenotype. These epigenetic modifications are reversible and various compounds/drugs targeting the epigenetic enzymes have been developed that are effective in cancer treatment. This chapter focuses on the epigenetic alterations in prostate cancer initiation and progression, listing different epigenetic biomarkers for diagnosis and prognosis of the disease and their potential as therapeutic targets. This chapter also summarizes different epigenetic drugs approved for prostate cancer therapy and the drugs available for clinical trials., (Copyright © 2024. Published by Elsevier Inc.)

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., (© 2022. The Author(s).)

The appropriate coordination between epigenetic regulators is essential for spatial and temporal regulation of gene expression and maintenance of cell identity. Cancer is a disease driven by both genetic and epigenetic alterations. The widespread dysregulation and reversible nature of epigenetic alterations confer cancer cells with vulnerabilities for therapeutic interventions. Over the past decades, remarkable progress has been made in developing drugs that target epigenetic regulators, with many drugs under evaluation in clinical trials. Here, we summarize the epigenetic drugs currently in clinical investigations and highlight the potentials and challenges in their implication to treat cancer. We also discuss the preclinical and clinical results of combination therapies with epigenetic drugs and other therapies such as targeted and immune-based therapies., (© 2021 Federation of European Biochemical Societies.)

Background: Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with limited treatment possibilities. Merkel cell tumors display with neuroendocrine features and Merkel cell polyomavirus (MCPyV) infection in the majority (80%) of patients. Although loss of histone H3 lysine 27 trimethylation (H3K27me3) has been shown during MCC tumorigenesis, epigenetic dysregulation has largely been overlooked., Methods: We conducted global DNA methylation profiling of clinically annotated MCC primary tumors, metastatic skin tumors, metastatic lymph node tumors, paired normal tissues, and two human MCC cell lines using the Illumina Infinium EPIC DNA methylation BeadArray platform., Results: Significant differential DNA methylation patterns across the genome are revealed between the four tissue types, as well as based on MCPyV status. Furthermore, 964 genes directly regulated by promoter or gene body DNA methylation were identified with high enrichment in neuro-related pathways. Finally, our findings suggest that loss of H3K27me3 occupancy in MCC is attributed to KDM6B and EZHIP overexpression as a consequence of promoter DNA hypomethylation., Conclusions: We have demonstrated specific DNA methylation patterns for primary MCC tumors, metastatic MCCs, and adjacent-normal tissues. We have also identified DNA methylation markers that not only show potential diagnostic or prognostic utility in MCC management, but also correlate with MCC tumorigenesis, MCPyV expression, neuroendocrine features, and H3K27me3 status. The identification of DNA methylation alterations in MCC supports the need for further studies to understand the clinical implications of epigenetic dysregulation and potential therapeutic targets in MCC., (© 2021. The Author(s).)

We demonstrate that DNA hypomethylating agent (HMA) treatment can directly modulate the anti-tumor response and effector function of CD8 + T cells. In vivo HMA treatment promotes CD8 + T cell tumor infiltration and suppresses tumor growth via CD8 + T cell-dependent activity. Ex vivo, HMAs enhance primary human CD8 + T cell activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T cell activation-related transcriptional networks, culminating with over-activation of NFATc1 short isoforms. Mechanistically, demethylation of an intragenic CpG island immediately downstream to the 3' UTR of the short isoform was associated with antisense transcription and alternative polyadenylation of NFATc1 short isoforms. High-dimensional single-cell mass cytometry analyses reveal a selective effect of HMAs on a subset of human CD8 + T cell subpopulations, increasing both the number and abundance of a granzyme B high , perforin high effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response., Competing Interests: Declaration of interests D.D.D.C. received research funds from Pfizer and Nektar Therapeutics. D.D.D.C. is a co-founder and shareholder of DNAMx, Inc. C.K. is employed by and owns stock, patents, and royalties with Roche. J.S. is a permanent scientific advisory board member for and owns stock in Surface Oncology., (Copyright © 2021 Elsevier Inc. All rights reserved.)

ZAR1, zygote arrest 1, is a zinc finger protein (C-terminus), which was initially identified in mouse oocytes. Later it was found that its expression is present in various human tissues e.g. lung and kidney. Interestingly, it was observed that in various tumour types the ZAR1 transcript is missing due to hypermethylation of its CpG island promoter, but not ZAR2. Since methylation of the ZAR1 promoter is described as a frequent event in tumourigenesis, ZAR1 could serve as a useful diagnostic marker in cancer screens. ZAR1 was described as a useful prognostic/diagnostic cancer marker for lung cancer, kidney cancer, melanoma and possibly liver carcinoma. Furthermore, ZAR1 was reactivated as a tumour suppressor by epigenetic therapy using CRISPR-dCas9 method. This method holds the potential to precisely target not only ZAR1 and reactivate tumour suppressors in a tailored cancer therapy. ZAR1 is highly conserved amongst vertebrates, especially its zinc finger, which is the relevant domain for its protein and RNA binding ability. ZAR1 is implicated in various cellular mechanisms including regulation of oocyte/embryo development, cell cycle control and mRNA binding, though little was known about the underlying mechanisms. ZAR1 was reported to regulate and activate translation through the binding to TCS translation control sequences in the 3'UTRs of its target mRNA the kinase WEE1. ZAR1 has a tumour suppressing function by inhibiting cell cycle progression. Here we review the current literature on ZAR1 focusing on structural, functional and epigenetic aspects. Characterising the cellular mechanisms that regulate the signalling pathways ZAR1 is involved in, could lead to a deeper understanding of tumour development and, furthermore, to new strategies in cancer treatment., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Epigenetic reprogramming using DNA demethylating drugs is a promising approach for cancer therapy, but its efficacy is highly dependent on the dosing regimen. Low-dose treatment for a prolonged period shows a remarkable therapeutic efficacy, despite its small demethylating effect. Here, we aimed to explore the mechanisms of how such low-dose treatment shows this remarkable efficacy by focusing on epigenetic reprograming at the single-cell level., Methods: Expression profiles in HCT116 cells treated with decitabine (DAC) were analyzed by single-cell RNA-sequencing (scRNA-seq). Functional consequences and DNA demethylation at the single-cell level were analyzed using cloned HCT116 cells after DAC treatment., Results: scRNA-seq revealed that DAC-treated cells had highly diverse expression profiles at the single-cell level, and tumor-suppressor genes, endogenous retroviruses, and interferon-stimulated genes were upregulated in random fractions of cells. DNA methylation analysis of cloned HCT116 cells revealed that, while only partial reduction of DNA methylation levels was observed in bulk cells, complete demethylation of specific cancer-related genes, such as cell cycle regulation, WNT pathway, p53 pathway, and TGF-β pathway, was observed, depending upon clones. Functionally, a clone with complete demethylation of CDKN2A (p16) had a larger fraction of cells with tetraploid than parental cells, indicating induction of cellular senescence due to normalization of cell cycle regulation., Conclusions: Epigenetic reprogramming of specific cancer-related pathways at the single-cell level is likely to underlie the remarkable efficacy of low-dose DNA demethylating therapy.

Uveal melanoma (UM), the most common intraocular malignancy in adults, is a rare subset of melanoma. Despite effective primary therapy, around 50% of patients will develop the metastatic disease. Several clinical trials have been evaluated for patients with advanced UM, though outcomes remain dismal due to the lack of efficient therapies. Epigenetic dysregulation consisting of aberrant DNA methylation, histone modifications, and small non-coding RNA expression, silencing tumor suppressor genes, or activating oncogenes, have been shown to play a significant role in UM initiation and progression. Given that there is no evidence any approach improves results so far, adopting combination therapies, incorporating a new generation of epigenetic drugs targeting these alterations, may pave the way for novel promising therapeutic options. Furthermore, the fusion of effector enzymes with nuclease-deficient Cas9 (dCas9) in clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) system equips a potent tool for locus-specific erasure or establishment of DNA methylation as well as histone modifications and, therefore, transcriptional regulation of specific genes. Both, CRISPR-dCas9 potential for driver epigenetic alterations discovery, and possibilities for their targeting in UM are highlighted in this review.

DNA methylation patterns are frequently altered in cancer cells as compared to normal cells. A large body of research associates these DNA methylation aberrations with cancer initiation and progression. Moreover, cancer cells seem to depend upon these aberrant DNA methylation profiles to thrive. Finally, DNA methylation modifications are reversible, highlighting the potential to target the global methylation patterns for cancer therapy. In this review, we will discuss the scientific and clinical aspects of DNA methylation in cancer. We will review the limited success of targeting DNA methylation in the clinic, the associated clinical challenges, the impact of novel DNA methylation inhibitors and how combination therapies are improving patient outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Multiple myeloma (MM) is a tumor of antibody producing plasmablasts/plasma cells that resides within the bone marrow (BM). In addition to the well-established role of genetic lesions and tumor-microenvironment interactions in the development of MM, deregulated epigenetic mechanisms are emerging as important in MM pathogenesis. Recently, MM sequencing and expression projects have revealed that mutations and copy number variations as well as deregulation in the expression of epigenetic modifiers are characteristic features of MM. In the past decade, several studies have suggested epigenetic mechanisms via DNA methylation, histone modifications and non-coding RNAs as important contributing factors in MM with impacts on disease initiation, progression, clonal heterogeneity and response to treatment. Herein we review the present view and knowledge that has accumulated over the past decades on the role of epigenetics in MM, with focus on the interplay between epigenetic mechanisms and the potential use of epigenetic inhibitors as future treatment modalities for MM., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder, typically of older adults, which is characterized by ineffective hematopoiesis, peripheral blood cytopenias and risk of progression to acute myeloid leukemia. Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm occurring in young children. The common denominator of these malignant myeloid disorders is the limited benefit of conventional chemotherapy and a particular responsiveness to epigenetic therapy with the DNA-hypomethylating agents 5-azacytidine (azacitidine) or decitabine. However, hypomethylating therapy does not eradicate the malignant clone in MDS or JMML and allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option. An emerging concept with intriguing potential is the combination of hypomethylating therapy and HSCT. Possible advantages include disease control with good tolerability during donor search and HSCT preparation, improved antitumoral alloimmunity, and reduced risk of relapse even with non-myeloablative regimens. Herein we review the current role of pre- and post-transplant therapy with hypomethylating agents in MDS and JMML., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

DNA methylation at cytosines followed by guanines, CpGs, forms one of the multiple layers of epigenetic mechanisms controlling and modulating gene expression through chromatin structure. It closely interacts with histone modifications and chromatin remodeling complexes to form the local genomic and higher-order chromatin landscape. DNA methylation is essential for proper mammalian development, crucial for imprinting and plays a role in maintaining genomic stability. DNA methylation patterns are susceptible to change in response to environmental stimuli such as diet or toxins, whereby the epigenome seems to be most vulnerable during early life. Changes of DNA methylation levels and patterns have been widely studied in several diseases, especially cancer, where interest has focused on biomarkers for early detection of cancer development, accurate diagnosis, and response to treatment, but have also been shown to occur in many other complex diseases. Recent advances in epigenome engineering technologies allow now for the large-scale assessment of the functional relevance of DNA methylation. As a stable nucleic acid-based modification that is technically easy to handle and which can be analyzed with great reproducibility and accuracy by different laboratories, DNA methylation is a promising biomarker for many applications.

Epigenetic modifications modulate chromatin states to regulate gene expression. Among them, DNA methylation and histone modifications play a crucial role in the establishment of the epigenome. In cancer, these epigenetic events may act in concert to repress tumor suppressor genes or promote oncogenic pathways. In the context of cancer initiation and progression, recruitment of DNA (cytosine-5)-methyltransferases to specific genomic regions is mainly mediated by histone epigenetic marks, transcription factors and co-regulators as part of a dynamic process. Herein, we will review these mechanisms and present state-of-the-art of DNA methylation, treatment and development of epigenetic cancer therapies targeting this epigenetic modification., (Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

DNA methylation and histone modifications determine renal programming and the development and progression of renal disease. The identification of the way in which the renal cell epigenome is altered by environmental modifiers driving the onset and progression of renal diseases has extended our understanding of the pathophysiology of kidney disease progression. In this review, we focus on current knowledge concerning the implications of epigenetic modifications during renal disease from early development to chronic kidney disease progression including renal fibrosis, diabetic nephropathy and the translational potential of identifying new biomarkers and treatments for the prevention and therapy of chronic kidney disease and end-stage kidney disease.

Epigenetic dysregulation is one of many factors that contribute to cancer development and progression. Numerous epigenetic alterations have been identified in urologic cancers including histone modifications, DNA methylation changes, and microRNA expression. Since these changes are reversible, efforts are being made to develop epigenetic drugs that restore the normal epigenetic patterns of cells, and many clinical trials are already underway to test their clinical potential. In this review we analyze multiple clinical trials (n=51) that test the efficacy of these drugs in patients with urologic cancers. The most frequently used epigenetic drugs were histone deacetylase inhibitors followed by antisense oligonucleotides, DNA methyltransferase inhibitors and histone demethylase inhibitors, the last of which are only being tested in prostate cancer. In more than 50% of the clinical trials considered, epigenetic drugs were used as part of combination therapy, which achieved the best results. The epigenetic regulation of some cancers is still matter of research but will undoubtedly open a window to new therapeutic approaches in the era of personalized medicine. The future of therapy for urological malignancies is likely to include multidrug regimens in which epigenetic modifying drugs will play an important role.

Purpose: Decitabine, a promising epi-immunotherapeutic agent has shown clinical responses in solid tumor patients, while the anti-tumor mechanisms were unclear. We aimed to investigate the immunomodulatory effect of decitabine in peripheral T cells., Experimental Design: We applied next-generation sequencing to investigate the complementarity-determining region 3 (CDR3) of the TCRβ gene, the diversity of which acts as the prerequisite for the host immune system to recognize the universal foreign antigens. We collected the peripheral blood mononuclear cells (PBMCs) from 4 patients, at baseline and after 2 cycles of low-dose decitabine therapy., Results: An increase of the unique productive sequences of the CDR3 of TCRβ was observed in all of the 4 patients after decitabine treatment, which was characterized by a lower abundance of expanded clones and increased TCR diversity compared with before decitabine treatment. Further analysis showed a tendency for CD4 T cells with an increased CD4/CD8 ratio in response to decitabine therapy. In addition, the genome-wide expression alterations confirmed the effects of decitabine on immune reconstitution, and the increase of TCR excision circles (TRECs) was validated., Conclusions: The low-dose DNMT inhibitor decitabine broadens the peripheral T cell repertoire, providing a novel role for the epigenetic modifying agent in anti-tumor immune enhancement., Competing Interests: None.

DNA methylation has been recognized as one of the most important epigenetic mechanisms regulating the expression and inhibition of genes giving rise to an organism's phenotype. It is hence of no surprise that when DNA methylation mechanisms are disrupted by intrinsic or extrinsic causes, the likelihood of tumourigenesis increases. Both hypermethylation and hypomethylation may predispose to cancer formation through aberrant inhibition or expression of particular genes and this is seen in different types of cancers, such as laryngeal squamous cell carcinoma and acute myeloid leukaemia. By increasing our knowledge and understanding of these epigenetic mechanisms, we will be able to develop diagnostic techniques such as methylation profiling, to screen for and detect aberrant methylation patterns which may predispose to cancer formation in our patients. This would enable early diagnosis and treatment which may also involve the use of drugs developed to provide directed epigenetic therapy, shifting away from the current trend which involves the use of radical anti-cancer therapy. These diagnostic and treatment options may be the future of cancer management.

Aberrant DNA methylation is a critical feature of cancer. Epigenetic therapy seeks to reverse these changes to restore normal gene expression. DNA demethylating agents, including 5-aza-2'-deoxycytidine (DAC), are currently used to treat certain leukemias, and can sensitize solid tumors to chemotherapy and immunotherapy. However, it has been difficult to pin the clinical efficacy of these agents to specific demethylation events, and the factors that contribute to the durability of response remain largely unknown. Here we examined the genome-wide kinetics of DAC-induced DNA demethylation and subsequent remethylation after drug withdrawal in breast cancer cells. We find that CpGs differ in both their susceptibility to demethylation and propensity for remethylation after drug removal. DAC-induced demethylation was most apparent at CpGs with higher initial methylation levels and further from CpG islands. Once demethylated, such sites exhibited varied remethylation potentials. The most rapidly remethylating CpGs regained >75% of their starting methylation within a month of drug withdrawal. These sites had higher pretreatment methylation levels, were enriched in gene bodies, marked by H3K36me3, and tended to be methylated in normal breast cells. In contrast, a more resistant class of CpG sites failed to regain even 20% of their initial methylation after 3 months. These sites had lower pretreatment methylation levels, were within or near CpG islands, marked by H3K79me2 or H3K4me2/3, and were overrepresented in sites that become aberrantly hypermethylated in breast cancers. Thus, whereas DAC-induced demethylation affects both endogenous and aberrantly methylated sites, tumor-specific hypermethylation is more slowly regained, even as normal methylation promptly recovers. Taken together, these data suggest that the durability of DAC response is linked to its selective ability to stably reset at least a portion of the cancer methylome.

Cervical cancer is the second most common cancer among women worldwide. About 528,000 women are diagnosed with cervical cancer contributing to around 266,000 deaths, across the globe every year. Out of these, the burden of 226,000 (85%) deaths occurs in the developing countries, who are less resource intensive to manage the disease. This is despite the fact that cervical cancer is amenable for early detection due to its long and relatively well-known natural history prior to its culmination as invasive disease. Infection with high risk human papillomavirus (hrHPVs) is essential but not sufficient to cause cervical cancer. Although it was thought that genetic mutations alone was sufficient to cause cervical cancer, the current epidemiological and molecular studies have shown that HPV infection along with genetic and epigenetic changes are frequently associated and essential for initiation, development and progression of the disease. Moreover, aberrant DNA methylation in host and HPV genome can be utilized not only as biomarkers for early detection, disease progression, diagnosis and prognosis of cervical cancer but also to design effective therapeutic strategies. In this review, we focus on recent studies on DNA methylation changes in cervical cancer and their potential role as biomarkers for early diagnosis, prognosis and targeted therapy., (Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Epigenetic silencing and inappropriate activation of gene expression are frequent events during the initiation and progression of cancer. These events involve a complex interplay between the hypermethylation of CpG dinucleotides within gene promoter and enhancer regions, the recruitment of transcriptional corepressors and the deacetylation and/or methylation of histone tails. These epigenetic regulators act in concert to block transcription or interfere with the maintenance of chromatin boundary regions. However, DNA/histone methylation and histone acetylation states are reversible, enzyme-mediated processes and as such, have emerged as promising targets for cancer therapy. This review will focus on the potential benefits and synergistic/additive effects of combining DNA-demethylating agents and histone deacetylase inhibitors or lysine-specific demethylase inhibitors together in epigenetic therapy for solid tumors and will highlight what is known regarding the mechanisms of action that contribute to the antitumor response., (© 2016 Elsevier Inc. All rights reserved.)

Background: Hepatocellular carcinoma is the fifth most common cancer worldwide, with poor prognosis and resistance to chemotherapy. This gives novel cancer treatment methods an overwhelming significance. Epigenetic therapy of cancer is useful in reversing some of the cancer defects because of reversibility of the epigenetic alterations. Non-protein coding transcripts are the major part of our transcriptome. MEG3 is a tumor suppressor long non-coding RNA being expressed in many normal tissues. Methylation of MEG3 promoter region elicits the decrease in its expression in hepatocellular cancer cells. Bioactive nutrients including curcumin offer great potential in altering DNA methylation status which is catalyzed via DNMT1, DNMT3A and 3B., Purpose: Herein, we aimed to study RNA-based epigenetic effects of dendrosomal curcumin (DNC) on hepatocellular cancer (HCC)., Study Design: To this end miRNA-dependent regulation of MEG3 expression under treatment with DNC was studied by evaluating the modulatory involvement of miR-29a for DNMT3A and 3B and miR-185 for DNMT1., Methods: We evaluated DNC entrance to HCC cells with the use of fluorescent characteristics of curcumin. Next we performed the MTT assay to evaluate DNC and dendrosome effects on HCC cell viability. The coding and non-coding genes expression analyses were done using quantitative-PCR., Results: In result we found that the DNC dependent overexpression of miR-29a and miR-185 (P < 0.01) can down-regulate the expression of DNMT1, 3A and 3B (P < 0.05) and subsequently overexpresses MEG3 (P < 0.05)., Conclusion: DNC potentially can induce DNA hypomethylation and reexpression of silenced tumor suppressor genes in HCC. These data suggest that DNC could be an effective choice for epigenetic therapy of HCC., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Clofarabine (2-chloro-2'-fluoro-2'-deoxyarabinosyladenine, ClF) is a second-generation 2'-deoxyadenosine analogue that is structurally related to cladribine (2-chloro-2'-deoxyadenosine, 2CdA) and fludarabine (9-beta-d-arabinosyl-2-fluoroadenine, F-ara-A). It demonstrates potent antitumour activity at much lower doses than parent compounds with high therapeutic efficacy in paediatric blood cancers. Our previous studies in breast cancer cells indicate that 2CdA and F-ara-A are involved in epigenetic regulation of gene transcription. We therefore investigated whether ClF influences methylation and expression of selected tumour suppressor genes, such as adenomatous polyposis coli (APC), phosphatase and tensin homologue (PTEN), and retinoic acid receptor beta 2 (RARbeta2), as well as expression of p53, p21 and DNA methyltransferase 1 (DNMT1) in MCF-7 and MDA-MB-231 breast cancer cell lines with different invasive potential. Promoter methylation and gene expression were estimated using methylation-sensitive restriction analysis (MSRA) and real-time PCR, respectively. ClF demonstrated potent growth inhibitory activity in MCF-7 and MDA-MB-231 cells after 96h treatment with IC50 determined as equal to 640nM and 50nM, respectively. In both breast cancer cell lines, ClF led to hypomethylation and up-regulation of APC, PTEN and RARbeta2 as well as increase in p21 expression. Only in non-invasive MCF-7 cells, these changes were associated with down-regulation of DNMT1. Our results provide first evidence of ClF implications in epigenetic regulation of transcriptional activity of selected tumour suppressor genes in breast cancer. It seems to be a new important element of ClF anticancer activity and may indicate its potential efficacy in epigenetic therapy of solid tumours, especially at early stages of carcinogenesis., (© 2013 Elsevier B.V. All rights reserved.)

The ten-eleven translocation enzymes catalyze the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, a distinct epigenetic mark that has an integral role in active demethylation. Genes that regulate the distribution and amount of 5-hydroxymethylcytosine in the genome could be suitable therapeutic targets to correct abnormal methylation in cancer. Here, we present an overview of the role of the 5-hydroxymethylcytosine pathway in human disease and discuss the emergence of innovative techniques that can map the distribution of 5-hydroxymethylcytosine at high resolution. In the context of current epigenetic therapies and by using recent functional studies, we propose plausible mechanisms to target the 5-hydroxymethylcytosine pathway in cancer. As the study of 5-hydroxymethylcytosine is still in its infancy, we provide future perspectives.

Although genetic, environmental, and lifestyle factors largely contribute to type 2 diabetes mellitus (T2DM) risk, the role of epigenetics in its pathogenesis is now well established. The epigenetic mechanisms in T2DM mainly consist of DNA methylation, histone modifications and regulation by noncoding RNAs (ncRNAs). For instance, DNA methylation at CpG islands in the promoter regions of specific genes encoding insulin signaling and glucose metabolism suppresses these genes. Modulating the enzyme mediators of these epigenetic marks aims to restore standard gene expression patterns and improve glycemic control. In targeting these epigenetic marks, using epigenetic drugs such as DNA methyltransferase (DNAMT), histone deacetylase (HDAC) and histone acetyltransferase (HAT) inhibitors has led to variable success in humans and experimental murine models. Specifically, the United States' Food and Drug Administration (US FDA) has approved DNAMT inhibitors like 5-azacytidine and 5-aza-2ʹ-deoxycytidine for use in diabetic retinopathy: a T2DM microvascular complication. These DNAMT inhibitors block the genes for methylation of mitochondrial superoxide dismutase 2 (SOD2) and matrix metallopeptidase 9 (MMP-9): the epigenetic marks in diabetic retinopathy. Traditional pharmacotherapy with metformin also have epigenetic effects in T2DM and positively alter disease outcomes when combined with epigenetic drugs like DNAMT and HDAC inhibitors, raising the prospect of using epigenetic therapy as a valuable adjunct to pharmacotherapy. However, introducing small interfering RNAs (siRNAs) in cells to silence specific target genes remains in the exploratory phase. Future research should focus on regulating gene expression in T2DM using long noncoding RNA (lncRNA) molecules, another type of ncRNA. This review discusses the epigenetics of T2DM and that of its macro- and microvascular complications, and the potential benefits of combining epigenetic therapy with pharmacotherapy for optimal results. [ABSTRACT FROM AUTHOR]

Tingyi Li,1,2 Yanwei Chen,1 Shuai Li1 1Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China; 2Dalian Medical University, Dalian, People’s Republic of ChinaCorrespondence: Shuai Li; Yanwei Chen, Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China, Email shuaili2015@outlook.com; chenyanweile@163.comAbstract: Epigenetic dysregulation can significantly trigger the onset and progression of various diseases, epigenetic therapy is a new treatment strategy by changing DNA methylation, histone modification, N6-methyladenosine, chromatin modification and other epigenetic modifications to regulate gene expression levels for therapeutic purposes. However, small-molecule epigenetic drugs face challenges in disease treatment, such as lack of selectivity, limited therapeutic efficacy, and insufficient safety. Nanomedicine delivery systems offer significant advantages in addressing these issues by enhancing drug targeting, improving bioavailability, and reducing nonspecific distribution. This help minimize side effects while increasing both therapeutic effectiveness and safety of epigenetic drugs. In this review, we focus on the mechanism and role of epigenetic regulatory factors in diseases, as well as the challenges faced by small molecule inhibitors in treatment strategies, especially the research advancements in epigenetic drug delivery systems, review and discuss the therapeutic potential and challenges of using nanotechnology to develop epigenetic drug delivery systems.Keywords: epigenetic therapy, DNA methylation, N6-methyladenosine, histone modification, nanomedicine delivery systems, nanotechnology

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]

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]

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.

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]

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]

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]

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.

Ovarian cancer (OC) is one of the most lethal gynecologic malignancies globally. In spite of positive responses to initial therapy, the overall survival rates of OC patients remain poor due to the development of drug resistance and consequent cancer recurrence. Indeed, intensive studies have been conducted to unravel the molecular mechanisms underlying OC therapeutic resistance. Besides, emerging evidence suggests a crucial role for epigenetic modifications, namely, DNA methylation, histone modifications, and non-coding RNA regulation, in the drug resistance of OC. These epigenetic modifications contribute to chemoresistance through various mechanisms, namely, upregulating the expression of multidrug resistance proteins (MRPs), remodeling of the tumor microenvironment, and deregulated immune response. Therefore, an in-depth understanding of the role of epigenetic mechanisms in clinical therapeutic resistance may improve the outcome of OC patients. In this review, we will discuss the epigenetic regulation of OC drug resistance and propose the potential clinical implications of epigenetic therapies to prevent or reverse OC drug resistance, which may inspire novel treatment options by targeting resistance mechanisms for drug-resistant OC patients. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is the second most common type of primary liver cancer. Due to its often-silent manifestation, sporadic nature, and typically late clinical presentation, it remains difficult to diagnose and lacks effective nonsurgical therapeutic options. Extensive research aiming in understanding the mechanisms underlying this disease have provided strong evidence for the significance of epigenetics contributing to its onset, progression, and dissemination. This dysregulation in a myriad of signaling pathways, leading to malignancy, spans altered deoxyribonucleic acid and histone methylation, histone acetylation, and chromatin remodeling, as well as genetic modifications in essential genes controlling these epigenetic processes. An advantage to epigenetic modifications is that they, compared with mutations, are reversible and can partially be controlled by inhibiting the responsible enzymatic machinery. This opens novel possibilities for developing new treatment modalities with benefit for CCA patients. In this article, we have reviewed the current status of epigenome modifications described in CCA, including the role of posttranslational histone modifications and chromatin remodeling, as well as novel advances in treatment options. [ABSTRACT FROM AUTHOR]

Uveitis is a sight-threatening intraocular inflammation, and the exact pathogenesis of uveitis is not yet clear. Recent studies, including multiple genome-wide association studies (GWASs), have identified genetic variations associated with the onset and progression of different types of uveitis, such as Vogt–Koyanagi–Harada (VKH) disease and Behcet’s disease (BD). However, epigenetic regulation has been shown to play key roles in the immunoregulation of uveitis, and epigenetic therapies are promising treatments for intraocular inflammation. In this review, we summarize recent advances in identifying epigenetic programs that cooperate with the physiology of intraocular immune responses and the pathology of intraocular inflammation. These attempts to understand the epigenetic mechanisms of uveitis may provide hope for the future development of epigenetic therapies for these devastating intraocular inflammatory conditions.

Melanoma is the deadliest form of skin cancer with rising incidence and mortality rates. Although early-stage melanoma is highly curable, advanced-stage melanoma is refractory to treatment. This underscores the importance of prevention and early detection as well as the need to improve treatment and prognostication of human melanoma. Elucidating the underlying mechanisms of the initiation and progression of human melanoma can help identify potential targets of intervention for prevention, diagnosis, therapy, and prognosis of this disease. Aberrant DNA methylation and histone modifications are the best-established epigenetic mechanisms of carcinogenesis. The occurrence of epigenetic changes prior to clinical diagnosis of cancer and their reversibility through pharmacologic/genetic approaches offer a promising avenue for basic and translational research on human melanoma. Candidate gene(s) or genome-wide aberrant DNA methylation and histone modifications have been observed in human melanoma tumor tissues and cell lines, and correlated to cellular and functional characteristics and/or clinicopathological features of this malignancy. The present review summarizes the published researches on aberrant DNA methylation and histone modifications in connection with human melanoma. Representative studies are highlighted to set forth the current state of knowledge, gaps in the knowledgebase, and future directions in these epigenetic fields of research. Examples of epigenetic therapy applied for human melanoma in vitro, and the challenges of its in vivo application for clinical treatment of solid tumors are discussed.

Background: Epigenetic mechanisms regulate chromatin accessibility patterns that govern interaction of transcription machinery with genes and their cis-regulatory elements. Mutations that affect epigenetic mechanisms are common in cancer. Because epigenetic modifications are reversible many anticancer strategies targeting these mechanisms are currently under development and in clinical trials. Main body: Here we review evidence suggesting that epigenetic therapeutics can deactivate immunosuppressive gene expression or reprogram tumor cells to activate antigen presentation mechanisms. In addition, the dysregulation of epigenetic mechanisms commonly observed in cancer may alter the immunogenicity of tumor cells and effectiveness of immunotherapies. Conclusions: Therapeutics targeting epigenetic mechanisms may be helpful to counter immune evasion and improve the effectiveness of immunotherapies. [ABSTRACT FROM AUTHOR]

Epigenetic alterations are associated with normal biological processes such as aging or differentiation. Changes in global epigenetic signatures, together with genetic alterations, are driving events in several diseases including cancer. Comparative studies of cancer and healthy tissues found alterations in patterns of DNA methylation, histone posttranslational modifications, and changes in chromatin accessibility. Driven by sophisticated, next-generation sequencing-based technologies, recent studies discovered cancer epigenomes to be dominated by epigenetic patterns already present in the cell-of-origin, which transformed into a neoplastic cell. Tumor-specific epigenetic changes therefore need to be redefined and factors influencing epigenetic patterns need to be studied to unmask truly disease-specific alterations. The underlying mechanisms inducing cancer-associated epigenetic alterations are poorly understood. Studies of mutated epigenetic modifiers, enzymes that write, read, or edit epigenetic patterns, or mutated chromatin components, for example oncohistones, help to provide functional insights on how cancer epigenomes arise. In this review, we highlight the importance and define challenges of proper control tissues and cell populations to exploit cancer epigenomes. We summarize recent advances describing mechanisms leading to epigenetic changes in tumorigenesis and briefly discuss advances in investigating their translational potential. [ABSTRACT FROM AUTHOR]

Esophageal cancer is a leading cause of cancer‐related deaths worldwide. In the past few years, the roles of epigenetics in cancer have been fully accepted. Recently, there has been an increased focus on epigenetic alterations underlying esophageal cancer carcinogenesis, with several epigenetic drug and RNA interference therapies being tested. However, the conclusion that epigenetic alterations are linked directly to an increased or decreased risk of esophageal cancer is less certain. Therefore, there is an urgent need to test novel epigenetic biomarkers for diagnostic and prognostic significance and to explore their potential as therapeutic targets. In this review, the discussion is concentrated on epigenetic alterations involving super‐enhancers, DNA methylation, histone modifications, and multiple noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), and their impact on tumor growth, invasion, metastasis, and drug resistance. Then specific instances of using epigenetic drugs, such as DNA methyltransferase and histone deacetylase inhibitors, to treat esophageal cancer are described. Recent developments in miRNA‐based therapeutic strategies, including antagomirs, lock nucleic acids, miRNA sponges, and microRNA replacement therapies, against esophageal cancer are also highlighted. [ABSTRACT FROM AUTHOR]