Search

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]

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]

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]

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]

Current studies show that approximately one-third of all cancer-related deaths are linked to diet and several cancer forms are preventable with balanced nutrition, due to dietary compounds being able to reverse epigenetic abnormalities. An appropriate diet in cancer patients can lead to changes in gene expression and enhance the efficacy of therapy. It has been demonstrated that nutraceuticals can act as powerful antioxidants at the cellular level as well as anticarcinogenic agents. This review is focused on the best studies on worldwide-available plant-derived nutraceuticals: curcumin, resveratrol, sulforaphane, indole-3-carbinol, quercetin, astaxanthin, epigallocatechin-3-gallate, and lycopene. These compounds have an enhanced effect on epigenetic changes such as histone modification via HDAC (histone deacetylase), HAT (histone acetyltransferase) inhibition, DNMT (DNA methyltransferase) inhibition, and non-coding RNA expression. All of these nutraceuticals are reported to positively modulate the epigenome, reducing cancer incidence. Furthermore, the current review addresses the issue of the low bioavailability of nutraceuticals and how to overcome the drawbacks related to their oral administration. Understanding the mechanisms by which nutraceuticals influence gene expression will allow their incorporation into an "epigenetic diet" that could be further capitalized on in the therapy of cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: BRCA1 and−2 are critical components of the homologous recombination pathway of DNA repair required to effectively repair DNA double strand breaks, leading to an increased cancer risk in patients with inherited BRCA mutations. An additional subset of cancers exhibit 'BRCAness', harboring repair defects stemming from mutations in non-BRCA DNA repair genes. Both BRCA-mutant cancers and cancers with a BRCAness phenotype are sensitive to PARP inhibitors, a class of cancer therapy drugs that inhibit the repair of DNA single strand breaks. To expand the use of PARP inhibitors to a larger group of patients, studies have focused on new combination strategies using agents that can induce BRCAness. This review focuses on the current status of drug-induced BRCAness in combination with PARP inhibitors to enhance cancer treatment. The poly(ADP-ribose) polymerase (PARP) family of proteins has been implicated in numerous cellular processes, including DNA repair, translation, transcription, telomere maintenance, and chromatin remodeling. Best characterized is PARP1, which plays a central role in the repair of single strand DNA damage, thus prompting the development of small molecule PARP inhibitors (PARPi) with the intent of potentiating the genotoxic effects of DNA damaging agents such as chemo- and radiotherapy. However, preclinical studies rapidly uncovered tumor-specific cytotoxicity of PARPi in a subset of cancers carrying mutations in the BReast CAncer 1 and 2 genes (BRCA1/2), which are defective in the homologous recombination (HR) DNA repair pathway, and several PARPi are now FDA-approved for single agent treatment in BRCA-mutated tumors. This phenomenon, termed synthetic lethality, has now been demonstrated in tumors harboring a number of repair gene mutations that produce a BRCA-like impairment of HR (also known as a 'BRCAness' phenotype). However, BRCA mutations or BRCAness is present in only a small subset of cancers, limiting PARPi therapeutic utility. Fortunately, it is now increasingly recognized that many small molecule agents, targeting a variety of molecular pathways, can induce therapeutic BRCAness as a downstream effect of activity. This review will discuss the potential for targeting a broad range of molecular pathways to therapeutically induce BRCAness and PARPi synthetic lethality. [ABSTRACT FROM AUTHOR]

by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC. Although VHL mutations are considered as drivers of ccRCC, they are not sufficient to cause the disease. Recent genome-wide sequencing studies of ccRCC have revealed that mutations of genes coding for epigenome modifiers and chromatin remodelers, including PBRM1, SETD2 and BAP1, are the most common somatic genetic abnormalities after VHL mutations in these tumors. Moreover, recent research has shed light on the extent of abnormal epigenome alterations in ccRCC tumors, including aberrant DNA methylation patterns, abnormal histone modifications and deregulated expression of non-coding RNAs. In this review, we discuss the epigenetic modifiers that are commonly mutated in ccRCC, and our growing knowledge of the cellular processes that are impacted by them. Furthermore, we explore new avenues for developing therapeutic approaches based on our knowledge of epigenome aberrations of ccRCC. [ABSTRACT FROM AUTHOR]

High-grade astrocytoma of WHO grade 4 termed glioblastoma multiforme (GBM) is a common human brain tumor with poor patient outcome. Astrocytoma demonstrates two known telomere maintenance mechanisms (TMMs) based on telomerase activity (TA) and on alternative lengthening of telomeres (ALT). ALT is associated with lower tumor grades and better outcome. In contrast to ALT, regulation of TA in tumors by direct mutation and epigenetic activation of the hTERT promoter is well established. Here, we summarize the genetic background of TMMs in non-malignant cells and in cancer, in addition to clinical and pathological features of gliomas. Furthermore, we present new evidence for epigenetic mechanisms (EMs) involved in regulation of ALT and TA with special emphasis on human diffuse gliomas as potential therapeutic drug targets. We discuss the role of TMM associated telomeric chromatin factors such as DNA and histone modifying enzymes and non-coding RNAs including microRNAs and long telomeric TERRA transcripts. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability, caused by CGG expansion over 200 repeats (full mutation, FM) at the 5' untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene and subsequent DNA methylation of the promoter region, accompanied by additional epigenetic histone modifications that result in a block of transcription and absence of the fragile X mental retardation protein (FMRP). The lack of FMRP, involved in multiple aspects of mRNA metabolism in the brain, is thought to be the direct cause of the FXS phenotype. Restoration of FMR1 transcription and FMRP production can be obtained in vitro by treating FXS lymphoblastoid cell lines with the demethylating agent 5-azadeoxycytidine, demonstrating that DNA methylation is key to FMR1 inactivation. This concept is strengthened by the existence of rare male carriers of a FM, who are unable to methylate the FMR1 promoter. These individuals produce limited amounts of FMRP and are of normal intelligence. Their inability to methylate the FMR1 promoter, whose cause is not yet fully elucidated, rescues them from manifesting the FXS. These observations demonstrate that a therapeutic approach to FXS based on the pharmacological reactivation of the FMR1 gene is conceptually tenable and worthy of being further pursued. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy. [ABSTRACT FROM AUTHOR]

Both genetic and epigenetic alterations can control the progression of cancer. Genetic alterations are impossible to reverse, while epigenetic alterations are reversible. This advantage suggests that epigenetic modifications should be preferred in therapy applications. DNA methyltransferases and histone deacetylases have become the primary targets for studies in epigenetic therapy. Some DNA methylation inhibitors and histone deacetylation inhibitors are approved by the US Food and Drug Administration as anti-cancer drugs. Therefore, the uses of epigenetic targets are believed to have great potential as a lasting favorable approach in treating breast cancer. [ABSTRACT FROM AUTHOR]

The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except for the DNA hypomethylation of some genes. Recently, we reported that the overexpression of cancer-promoting genes in ovarian cancer is associated with the loss of repressive histone modifications. This discovery suggested that epigenetic derepression may contribute to ovarian tumorigenesis by constituting a possible mechanism for the overexpression of oncogenes or cancer-promoting genes in tumors. The emerging importance of epigenetic aberrations in tumor initiation and in the regulation of cancer-initiating cells, suggests that epigenetically regulated genes may be promising therapeutic targets and biomarkers. Given that the current challenges in ovarian cancer include the identification of biomarkers for early cancer detection and the discovery of novel therapeutic targets for patients with recurrent malignancies undergoing chemotherapy, understanding the epigenetic changes that occur in ovarian cancer is crucial. This review looks at epigenetic mechanisms involved in the regulation of cancer-associated genes, including the contribution of epigenetic derepression to the activation of cancer-associated genes in ovarian cancer. In addition, possible epigenetic therapies targeting epigenetically dysregulated genes are discussed. A better understanding of the epigenetic changes in ovarian cancer will contribute to the improvement of patient outcomes. [ABSTRACT FROM AUTHOR]

Recurrent high-grade serous ovarian cancer (HGSC) is clinically very challenging and prematurely shortens patients' lives. Recurrent ovarian cancer is characterized by high tumor heterogeneity; therefore, it is susceptible to epigenetic therapy in classic 2D tissue culture and rodent models. Unfortunately, this success has not translated well into clinical trials. Utilizing a 3D spheroid model over a period of weeks, we were able to compare the efficacy of classic chemotherapy and epigenetic therapy on recurrent ovarian cancer cells. Unexpectedly, in our model, a single dose of paclitaxel alone caused the exponential growth of recurrent high-grade serous epithelial ovarian cancer over a period of weeks. In contrast, this effect is not only opposite under treatment with panobinostat, but panobinostat reverses the repopulation of cancer cells following paclitaxel treatment. In our model, we also demonstrate differences in the drug-treatment sensitivity of classic chemotherapy and epigenetic therapy. Moreover, 3D-derived ovarian cancer cells demonstrate induced proliferation, migration, invasion, cancer colony formation and chemoresistance properties after just a single exposure to classic chemotherapy. To the best of our knowledge, this is the first evidence demonstrating a critical contrast between short and prolonged post-treatment outcomes following classic chemotherapy and epigenetic therapy in recurrent high-grade serous ovarian cancer in 3D culture. [ABSTRACT FROM AUTHOR]

The suppressor of cytokine signaling 1 (SOCS1) is a tumor suppressor gene found to be hypermethylated in cancers. It is involved in the oncogenic transformation of cirrhotic liver tissues. Here, we investigated the clinical relevance of SOCS1 methylation and modulation upon epigenetic therapy in diverse cellular populations of hepatocellular carcinoma (HCC). HCC clinical specimens were evaluated for SOCS1 methylation and mRNA expression. The effect of 5-Azacytidine (5-AZA), a demethylation agent, was assessed in different subtypes of HCC cells. We demonstrated that the presence of SOCS1 methylation was significantly higher in HCC compared to peri-HCC and non-tumoral tissues (52% vs. 13% vs. 14%, respectively, p < 0.001). In vitro treatment with a non-toxic concentration of 5-AZA significantly reduced DNMT1 protein expression for stromal subtype lines (83%, 73%, and 79%, for HLE, HLF, and JHH6, respectively, p < 0.01) compared to cancer stem cell (CSC) lines (17% and 10%, for HepG2 and Huh7, respectively), with the strongest reduction in non-tumoral IHH cells (93%, p < 0.001). 5-AZA modulated the SOCS1 expression in different extents among the cells. It was restored in CSC HCC HepG2 and Huh7 more efficiently than sorafenib. This study indicated the relevance of SOCS1 methylation in HCC and how cellular heterogeneity influences the response to epigenetic therapy. [ABSTRACT FROM AUTHOR]

Epigenetic alterations have emerged as essential contributors in the pathogenesis of various human diseases, including cutaneous melanoma (CM). Unlike genetic changes, epigenetic modifications are highly dynamic and reversible and thus easy to regulate. Here, we present a comprehensive review of the latest research findings on the role of genetic and epigenetic alterations in CM initiation and development. We believe that a better understanding of how aberrant DNA methylation and histone modifications, along with other molecular processes, affect the genesis and clinical behavior of CM can provide the clinical management of this disease a wide range of diagnostic and prognostic biomarkers, as well as potential therapeutic targets that can be used to prevent or abrogate drug resistance. We will also approach the modalities by which these epigenetic alterations can be used to customize the therapeutic algorithms in CM, the current status of epi-therapies, and the preliminary results of epigenetic and traditional combinatorial pharmacological approaches in this fatal disease. [ABSTRACT FROM AUTHOR]

Epigenetic therapies remain a promising, but still not widely used, approach in the management of patients with cancer. To date, the efficacy and use of epigenetic therapies has been demonstrated primarily in the management of haematological malignancies, with limited supportive data in solid malignancies. The most studied epigenetic therapies in breast cancer are those that target DNA methylation and histone modification; however, none have been approved for routine clinical use. The majority of pre-clinical and clinical studies have focused on triple negative breast cancer (TNBC) and hormone-receptor positive breast cancer. Even though the use of epigenetic therapies alone in the treatment of breast cancer has not shown significant clinical benefit, these therapies show most promise in use in combinations with other treatments. With improving technologies available to study the epigenetic landscape in cancer, novel epigenetic alterations are increasingly being identified as potential biomarkers of response to conventional and epigenetic therapies. In this review, we describe epigenetic targets and potential epigenetic biomarkers in breast cancer, with a focus on clinical trials of epigenetic therapies. We describe alterations to the epigenetic landscape in breast cancer and in treatment resistance, highlighting mechanisms and potential targets for epigenetic therapies. We provide an updated review on epigenetic therapies in the pre-clinical and clinical setting in breast cancer, with a focus on potential real-world applications. Finally, we report on the potential value of epigenetic biomarkers in diagnosis, prognosis and prediction of response to therapy, to guide and inform the clinical management of breast cancer patients.

Gynecological cancers (GCs) are currently among the major threats to female health. Moreover, there are different histologic subtypes of these cancers, which are defined as 'rare' due to an annual incidence of <6 per 100,000 women. The majority of these tend to be associated with a poor prognosis. Long non-coding RNAs (lncRNAs) play a critical role in the normal development of organisms as well as in tumorigenesis. LncRNAs can be classified into tumor suppressor genes or oncogenes, depending on their function within the cellular context and the signaling pathways in which they are involved. These regulatory RNAs are potential therapeutic targets for cancer due to their tissue and tumor specificity. However, there still needs to be a deeper understanding of the mechanisms by which lncRNAs are involved in the regulation of numerous biological functions in humans, both in normal health and disease. The lncRNA Mortal Obligate RNA Transcript (MORT; alias ZNF667-AS1) has been identified as a tumor-related lncRNA. ZNF667-AS1 gene, located in the human chromosome region 19q13.43, has been shown to be silenced by DNA hypermethylation in several cancers. In this review, we report on the biological functions of ZNF667-AS1 from recent studies and describe the regulatory functions of ZNF667-AS1 in human disease, including cancer. Furthermore, we discuss the emerging insights into the potential role of ZNF667-AS1 as a biomarker and novel therapeutic target in cancer, including GCs (ovarian, cervical, and endometrial cancers). [ABSTRACT FROM AUTHOR]

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. This review focuses on the widespread therapeutic potential of CBD with regard to enhanced wound healing, lowered toxicity profiles of chemotherapeutics, and augmented antitumorigenic effects. The current literature is sparse with regard to determining the clinically relevant concentrations of CBD given the biphasic nature of the compound's response. Therefore, there is an imminent need for further dose-finding studies in order to determine the optimal dose of CBD for both intermittent and regular users. We address the potential influence of regular or occasional CBD usage on therapeutic outcomes in ovarian cancer patients. Additionally, as the development of chemoresistance in ovarian cancer results in treatment failure, the potential for CBD to augment the efficacy of conventional chemotherapeutic and epigenetic drugs is a topic of significant importance. Our review is focused on the widespread therapeutic potential of CBD and whether or not a synergistic role exists in combination with epigenetic and classic chemotherapy medications. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review, the history of RNA interference discovery and current knowledge about microRNA biogenesis and post-transcriptional regulation of gene expression is summarized, with a special focus on microRNA clusters and families. Further, strong interplay between microRNAs and basic epigenetic mechanisms, such as DNA methylation and histone modifications, are introduced and associated with deregulated expression of microRNAs during tumor development. Finally, novel strategies for epigenetic-based therapies are discussed. MicroRNAs are small non-coding single-stranded RNA molecules regulating gene expression on a post-transcriptional level based on the seed sequence similarity. They are frequently clustered; thus, they are either simultaneously transcribed into a single polycistronic transcript or they may be transcribed independently. Importantly, microRNA families that contain the same seed region and thus target related signaling proteins, may be localized in one or more clusters, which are in a close relationship. MicroRNAs are involved in basic physiological processes, and their deregulation is associated with the origin of various pathologies, including solid tumors or hematologic malignancies. Recently, the interplay between the expression of microRNA clusters and families and epigenetic machinery was described, indicating aberrant DNA methylation or histone modifications as major mechanisms responsible for microRNA deregulation during cancerogenesis. In this review, the most studied microRNA clusters and families affected by hyper- or hypomethylation as well as by histone modifications are presented with the focus on particular mechanisms. Finally, the diagnostic and prognostic potential of microRNA clusters and families is discussed together with technologies currently used for epigenetic-based cancer therapies. [ABSTRACT FROM AUTHOR]

Cancer development involves both genetic and epigenetic alterations. Aberrant epigenetic modifications are reversible, allowing excellent opportunities for therapeutic intervention. Nowadays, several epigenetic drugs are used worldwide to treat, e.g., myelodysplastic syndromes and leukemias. However, overcoming resistance and widening the therapeutic profiles are the most important challenges faced by traditional epigenetic drugs. Recently, novel approaches to epigenetic therapies have been proposed. Next-generation epigenetic drugs, with longer half-life and better bioavailability, are being developed and tested. Since epigenetic phenomena are interdependent, treatment modalities include co-administration of two different epigenetic drugs. In order to sensitize cancer cells to chemotherapy, epigenetic drugs are administered prior to chemotherapy, or both epigenetic drug and chemotherapy are used together to achieve synergistic effects and maximize treatment efficacy. The combinations of epigenetic drug with immunotherapy are being tested, because they have proved to enhance antitumor immune responses. The next approach involves targeting the metabolic causes of epigenetic changes, i.e., enzymes which, when mutated, produce oncometabolites. Finally, epigenome editing makes it possible to modify individual chromatin marks at a defined region with unprecedented specificity and efficiency. This review summarizes the above attempts in fulfilling the promise of epigenetic drugs in the effective cancer treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Evidence has emerged implicating epigenetic alterations in inflammatory breast cancer (IBC) origin and progression. IBC is a rare and rapidly progressing disease, considered the most aggressive type of breast cancer (BC). At clinical presentation, IBC is characterized by diffuse erythema, skin ridging, dermal lymphatic invasion, and peau d'orange aspect. The widespread distribution of the tumor as emboli throughout the breast and intra- and intertumor heterogeneity is associated with its poor prognosis. In this review, we highlighted studies documenting the essential roles of epigenetic mechanisms in remodeling chromatin and modulating gene expression during mammary gland differentiation and the development of IBC. Compiling evidence has emerged implicating epigenetic changes as a common denominator linking the main risk factors (socioeconomic status, environmental exposure to endocrine disruptors, racial disparities, and obesity) with IBC development. DNA methylation changes and their impact on the diagnosis, prognosis, and treatment of IBC are also described. Recent studies are focusing on the use of histone deacetylase inhibitors as promising epigenetic drugs for treating IBC. All efforts must be undertaken to unravel the epigenetic marks that drive this disease and how this knowledge could impact strategies to reduce the risk of IBC development and progression. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer is an aggressive disease frequently associated with resistance to chemotherapy. Evidence supports that small molecules showing DNA methyltransferase inhibitory activity (DNMTi) are important to sensitize cancer cells to cytotoxic agents, in part, by reverting the acquired epigenetic changes associated with the resistance to therapy. The present study aimed to evaluate if chemical compounds derived from propolis could act as epigenetic drugs (epi-drugs). We selected three phenolic acids (caffeic, dihydrocinnamic, and p-coumaric) commonly detected in propolis and the (−)-epigallocatechin-3-gallate (EGCG) from green tea, which is a well-known DNA demethylating agent, for further analysis. The treatment with p-coumaric acid and EGCG significantly reduced the cell viability of four triple-negative breast cancer cell lines (BT-20, BT-549, MDA-MB-231, and MDA-MB-436). Computational predictions by molecular docking indicated that both chemicals could interact with the MTAse domain of the human DNMT1 and directly compete with its intrinsic inhibitor S-Adenosyl-l-homocysteine (SAH). Although the ethanolic extract of propolis (EEP) did not change the global DNA methylation content, by using MS-PCR (Methylation-Specific Polymerase Chain Reaction) we demonstrated that EEP and EGCG were able to partly demethylate the promoter region of RASSF1A in BT-549 cells. Also, in vitro treatment with EEP altered the RASSF1 protein expression levels. Our data indicated that some chemical compound present in the EEP has DNMTi activity and can revert the epigenetic silencing of the tumor suppressor RASSF1A. These findings suggest that propolis are a promising source for epi-drugs discovery. [ABSTRACT FROM AUTHOR]

In this study, we describe poly (lactic-co-glycolic) acid (PLGA)-based nanoparticles that combine photothermal therapy (PTT) with epigenetic therapy for melanoma. Specifically, we co-encapsulated indocyanine green (ICG), a PTT agent, and Nexturastat A (NextA), an epigenetic drug within PLGA nanoparticles (ICG-NextA-PLGA; INAPs). We hypothesized that combining PTT with epigenetic therapy elicits favorable cytotoxic and immunomodulatory responses that result in improved survival in melanoma-bearing mice. We utilized a nanoemulsion synthesis scheme to co-encapsulate ICG and NextA within stable and monodispersed INAPs. The INAPs exhibited concentration-dependent and near-infrared (NIR) laser power-dependent photothermal heating characteristics, and functioned as effective single-use agents for PTT of melanoma cells in vitro. The INAPs functioned as effective epigenetic therapy agents by inhibiting the expression of pan-histone deacetylase (HDAC) and HDAC6-specific activity in melanoma cells in vitro. When used for both PTT and epigenetic therapy in vitro, the INAPs increased the expression of co-stimulatory molecules and major histocompatibility complex (MHC) Class I in melanoma cells relative to controls. These advantages persisted in vivo in a syngeneic murine model of melanoma, where the combination therapy slowed tumor progression and improved median survival. These findings demonstrate the potential of INAPs as agents of PTT and epigenetic therapy for melanoma. [ABSTRACT FROM AUTHOR]

A new exciting area in cancer research is the study of cancer stem cells (CSCs) and the translational implications for putative epigenetic therapies targeted against them. Accumulating evidence of the effects of epigenetic modulating agents has revealed their dramatic consequences on cellular reprogramming and, particularly, reversing cancer stemness characteristics, such as self-renewal and chemoresistance. Lysine specific demethylase 1 (LSD1/KDM1A) plays a well-established role in the normal hematopoietic and neuronal stem cells. Overexpression of LSD1 has been documented in a variety of cancers, where the enzyme is, usually, associated with the more aggressive types of the disease. Interestingly, recent studies have implicated LSD1 in the regulation of the pool of CSCs in different leukemias and solid tumors. However, the precise mechanisms that LSD1 uses to mediate its effects on cancer stemness are largely unknown. Herein, we review the literature on LSD1's role in normal and cancer stem cells, highlighting the analogies of its mode of action in the two biological settings. Given its potential as a pharmacological target, we, also, discuss current advances in the design of novel therapeutic regimes in cancer that incorporate LSD1 inhibitors, as well as their future perspectives. [ABSTRACT FROM AUTHOR]

Histone ubiquitination is a critical epigenetic mechanism regulating DNA-driven processes such as gene transcription and DNA damage repair. Importantly, the cellular machinery regulating histone ubiquitination is frequently altered in cancers. Moreover, aberrant histone ubiquitination can drive oncogenesis by altering the expression of tumor suppressors and oncogenes, misregulating cellular differentiation and promoting cancer cell proliferation. Thus, targeting aberrant histone ubiquitination may be a viable strategy to reprogram transcription in cancer cells, in order to halt cellular proliferation and induce cell death, which is the basis for the ongoing development of therapies targeting histone ubiquitination. In this review, we present the normal functions of histone H2A and H2B ubiquitination and describe the role aberrant histone ubiquitination has in oncogenesis. We also describe the key benefits and challenges associated with current histone ubiquitination targeting strategies. As these strategies are predicted to have off-target effects, we discuss additional efforts aimed at developing synthetic lethal strategies and epigenome editing tools, which may prove pivotal in achieving effective and selective therapies targeting histone ubiquitination, and ultimately improving the lives and outcomes of those living with cancer. [ABSTRACT FROM AUTHOR]

The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except for the DNA hypomethylation of some genes. Recently, we reported that the overexpression of cancer-promoting genes in ovarian cancer is associated with the loss of repressive histone modifications. This discovery suggested that epigenetic derepression may contribute to ovarian tumorigenesis by constituting a possible mechanism for the overexpression of oncogenes or cancer-promoting genes in tumors. The emerging importance of epigenetic aberrations in tumor initiation and in the regulation of cancer-initiating cells, suggests that epigenetically regulated genes may be promising therapeutic targets and biomarkers. Given that the current challenges in ovarian cancer include the identification of biomarkers for early cancer detection and the discovery of novel therapeutic targets for patients with recurrent malignancies undergoing chemotherapy, understanding the epigenetic changes that occur in ovarian cancer is crucial. This review looks at epigenetic mechanisms involved in the regulation of cancer-associated genes, including the contribution of epigenetic derepression to the activation of cancer-associated genes in ovarian cancer. In addition, possible epigenetic therapies targeting epigenetically dysregulated genes are discussed. A better understanding of the epigenetic changes in ovarian cancer will contribute to the improvement of patient outcomes.

Both genetic and epigenetic alterations can control the progression of cancer. Genetic alterations are impossible to reverse, while epigenetic alterations are reversible. This advantage suggests that epigenetic modifications should be preferred in therapy applications. DNA methyltransferases and histone deacetylases have become the primary targets for studies in epigenetic therapy. Some DNA methylation inhibitors and histone deacetylation inhibitors are approved by the US Food and Drug Administration as anti-cancer drugs. Therefore, the uses of epigenetic targets are believed to have great potential as a lasting favorable approach in treating breast cancer.