Cancer Epigenetics Research Articles

Lysine Methyltransferases Signaling: Histones are Just the Tip of the Iceberg.

Protein lysine methylation is a functionally diverse post-translational modification involved in various major cellular processes. Lysine methylation can modulate proteins activity, stability, localization, and/or interaction, resulting in specific downstream signaling and biological outcomes. Lysine methylation is a dynamic and fine-tuned process, deregulation of which often leads to human pathologies. In particular, the lysine methylome and its associated signaling network can be linked to carcinogenesis and cancer progression. Histone modifications and chromatin regulation is a major aspect of lysine methylation importance, but increasing evidence suggests that a high relevance and impact of non-histone lysine methylation signaling has emerged in recent years. In this review, we draw an updated picture of the current scientific knowledge regarding non-histone lysine methylation signaling and its implication in physiological and pathological processes. We aim to demonstrate the significance of lysine methylation as a major and yet underestimated posttranslational modification, and to raise the importance of this modification in both epigenetic and cellular signaling by focusing on the observed activities of SET- and 7β-strandcontaining human lysine methyltransferases. Recent evidence suggests that what has been observed so far regarding lysine methylation's implication in human pathologies is only the tip of the iceberg. Therefore, the exploration of the "methylome network" raises the possibility to use these enzymes and their substrates as promising new therapeutic targets for the development of future epigenetic and methyllysine signaling cancer treatments.

Digging Deeper into Breast Cancer Epigenetics: Insights from Chemical Inhibition of Histone Acetyltransferase TIP60 In Vitro.

Breast cancer is often sporadic due to several factors. Among them, the deregulation of epigenetic proteins may be involved. TIP60 or KAT5 is an acetyltransferase that regulates gene transcription through the chromatin structure. This pleiotropic protein acts in several cellular pathways by acetylating proteins. RNA and protein expressions of TIP60 were shown to decrease in some breast cancer subtypes, particularly in triple-negative breast cancer (TNBC), where a low expression of TIP60 was exhibited compared with luminal subtypes. In this study, the inhibition of the residual activity of TIP60 in breast cancer cell lines was investigated by using two chemical inhibitors, TH1834 and NU9056, first on the acetylation of the specific target, lysine 4 of histone 3 (H3K4) by immunoblotting, and second, by chromatin immunoprecipitation (ChIP)-qPCR (-quantitative Polymerase Chain Reaction). Subsequently, significant decreases or a trend toward decrease of H3K4ac in the different chromatin compartments were observed. In addition, the expression of 48 human nuclear receptors was studied with TaqMan Low-Density Array in these breast cancer cell lines treated with TIP60 inhibitors. The statistical analysis allowed us to comprehensively characterize the androgen receptor and NR3C2 receptors in TNBC cell lines after TH1834 or NU9056 treatment. The understanding of the residual activity of TIP60 in the evolution of breast cancer might be a major asset in the fight against this disease, and could allow TIP60 to be used as a biomarker or therapeutic target for breast cancer progression in the future.

Nanoparticle-based Drug Delivery Systems for Targeted Epigenetics Cancer Therapy

This review summarizes the epigenetic mechanisms of deoxyribonucleic acid (DNA) methylation, histone modifications in cancer and the epigenetic modifications in cancer therapy. Due to their undesired side effects, the use of epigenetic drugs as chemo-drugs in cancer therapies is limited. The drug delivery system opens a door for minimizing these side effects and achieving greater therapeutic benefits. The limitations of current epigenetic therapies in clinical cancer treatment and the advantages of using drug delivery systems for epigenetic agents are also discussed. Combining drug delivery systems with epigenetic therapy is a promising approach to reaching a high therapeutic index and minimizing the side effects.

Targeting the epigenetic regulation of antitumour immunity.

Dysregulation of the epigenome drives aberrant transcriptional programmes that promote cancer onset and progression. Although defective gene regulation often affects oncogenic and tumour-suppressor networks, tumour immunogenicity and immune cells involved in antitumour responses may also be affected by epigenomic alterations. This could have important implications for the development and application of both epigenetic therapies and cancer immunotherapies, and combinations thereof. Here, we review the role of key aberrant epigenetic processes - DNA methylation and post-translational modification of histones - in tumour immunogenicity, as well as the effects of epigenetic modulation on antitumour immune cell function. We emphasize opportunities for small-molecule inhibitors of epigenetic regulators to enhance antitumour immune responses, and discuss the challenges of exploiting the complex interplay between cancer epigenetics and cancer immunology to develop treatment regimens combining epigenetic therapies with immunotherapies.

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials.

Chemotherapy is one of the most established and effective treatments for almost all types of cancer. However, the elevated toxicity due to the non-tumor-associated effects, development of secondary malignancies, infertility, radiation-induced fibrosis and resistance to treatment limit the effectiveness and safety of treatment. In addition, these multiple factors significantly impact quality of life. Over the last decades, our increased understanding of cancer epigenetics has led to new therapeutic approaches and the promise of improved patient outcomes. Epigenetic alterations are commonly found in cancer, especially the increased expression and activity of histone deacetylases (HDACs). Dysregulation of HDACs are critical to the development and progression of the majority of tumors. Hence, HDACs inhibitors (HDACis) were developed and now represent a very promising treatment strategy. The use of HDACis as monotherapy has shown very positive pre-clinical results, but clinical trials have had only limited success. However, combinatorial regimens with other cancer drugs have shown synergistic effects both in pre-clinical and clinical studies. At the same time, these combinations have enhanced the efficacy, reduced the toxicity and tumor resistance to therapy. In this review, we will examine examples of HDACis used in combination with other cancer drugs and highlight the synergistic effects observed in recent preclinical and clinical studies.

Targeting Epigenetics in Lung Cancer.

The epigenetic landscape, which in part includes DNA methylation, chromatin organization, histone modifications, and noncoding RNA regulation, greatly contributes to the heterogeneity that makes developing effective therapies for lung cancer challenging. This review will provide an overview of the epigenetic alterations that have been implicated in all aspects of cancer pathogenesis and progression as well as summarize clinical applications for targeting epigenetics in the treatment of lung cancer.

Aberrant Methylation of LINE-1 Transposable Elements: A Search for Cancer Biomarkers.

Cancer remains one of the main causes of human mortality despite significant progress in its diagnostics and therapy achieved in the past decade. Massive hypomethylation of retrotransposons, in particular LINE-1, is considered a hallmark of most malignant transformations as it results in the reactivation of retroelements and subsequent genomic instability. Accumulating data on LINE-1 aberrant methylation in different tumor types indicates its significant role in cancer initiation and progression. However, direct evidence that LINE-1 activation can be used as a cancer biomarker is still limited. The objective of this review was to critically evaluate the published results regarding the diagnostic/prognostic potential of the LINE-1 methylation status in cancer. Our analysis indicates that LINE-1 hypomethylation is a promising candidate biomarker of cancer development, which, however, needs validation in both clinical and laboratory studies to confirm its applicability to different cancer types and/or stages. As LINE-1 is present in multiple cell-free copies in blood, it has advantages over single-copy genes regarding perspectives of using its methylation status as an epigenetic cancer biomarker for cell-free DNA liquid biopsy.

Mutual Regulation of microRNAs and Epigenetics in Human Cancers

Mutual Regulation of microRNAs and Epigenetics in Human Cancers

Epigenetic plasticity, selection, and tumorigenesis.

Epigenetic processes converge on chromatin in order to direct a cell's gene expression profile. This includes both maintaining a stable cell identity, but also priming the cell for specific controlled transitions, such as differentiation or response to stimuli. In cancer, this normally tight control is often disrupted, leading to a wide scale hyper-plasticity of the epigenome and allowing stochastic gene activation and silencing, cell state transition, and potentiation of the effects of genetic lesions. Many of these epigenetic disruptions will confer a proliferative advantage to cells, allowing for a selection process to occur and leading to tumorigenesis even in the case of reversible or unstable epigenetic states. This review seeks to highlight how the fundamental epigenetic shifts in cancer contribute to tumorigenesis, and how understanding an integrated view of cancer genetics and epigenetics may more effectively guide research and treatment.

Abstract 1251: Epigenetics in early onset colorectal cancer (EOCRC)

Abstract Colorectal cancer (CRC) incidence rates have increased among young adults while the rates have decreased among older adults over 50 years of age. While the etiology of the growing prevalence of young adults with newly diagnosed CRC is unknown, there has been growing interest in the roles implicated for diabetes, obesity, environmental changes, and epigenetics. Among the epigenetic marks implicated in EOCRC, the most widely studied are the global DNA hypomethylation. Using mouse studies, our group has demonstrated that DNA methylation as an epigenetic mechanism to control gene expression is essential to postnatal development. We have discovered a key set of genes that undergo epigenetic changes in colonic epithelial stem cells, and these changes are stable over a lifetime. We have shown that the gut microbiome influences this process. Importantly, perturbation of established intestinal DNA methylation leads to accelerated intestinal tumor development. To translate our mechanistic studies in the animal model to humans, we have confirmed these CpG loci that are concordant between the two species (i.e. homologous regions and/or conserved CpG islands). Here, we hypothesize that the dysregulation of developmentally programmed intestinal DNA methylation is associated with enhanced susceptibility to colon cancer in young adult. We have identified a population of patients within the Harris Health and Baylor College of Medicine system under the age of 50 with mismatch repair stable colorectal adenocarcinoma. Patient characteristics including age, sex, race, and primary tumor profile (stage at diagnosis, histology, and RAS status) have been defined. Using a panel of 6 genes and bisulfite pyrosequencing for quantitative assessment of DNA methylation, we compared the level of methylation in EOCRC tumors to paired normal adjacent tissues as well as normal adult tissue (age 50 or greater) to traditional CRC tumors. Our preliminary data suggest hypermethylation patterns are distinct in patients of EOCRC relative to traditional CRC. Our ultimate goal is to better understand the etiology of EOCRC in order to devise better prevention and treatment strategies for EOCRC. Citation Format: Karen Riggins, Benjamin Musher, Michael Scheurer, Li Yang, Patricia Castro, Neda Zarrin-Khameh, Lanlan Shen. Epigenetics in early onset colorectal cancer (EOCRC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1251.

Abstract 3214: BART: An integrative bioinformatics toolkit and web server for functional transcription factor prediction

Abstract The goal of this bioinformatics tool is to predict functional transcription factors (TFs) from various queries of target genomic features. TFs play a key role in regulating gene expression in a dynamic chromatin structure. From a target gene set or a genomic region set, it is challenging to identify functional TFs that regulate these genes or bind in these regions, because of complexity of enhancer distributions and insufficient specificity of DNA sequence motifs. Here, we present BART (Binding Analysis for Regulation of Transcription), an interactive bioinformatics toolkit and web server to predict functional TFs that regulate a set of co-regulated genes or associate with a genomic profile. From a gene set, BART first uses a machine learning approach to generate a genome-wide cis-regulatory profile by leveraging hundreds of publicly available ChIP-seq profiles for active enhancer histone mark H3K27ac and DNase-seq profiles for genome-wide cis-regulatory elements. Then it identifies a list of TFs whose binding profiles most correlate with the cis-regulatory profile by comparing with tens of thousands of ChIP-seq datasets. BART can also identify TFs associated with differential chromatin interaction from a pair of three-dimensional (3D) genomic datasets, such as Hi-C. BART integrates over 12,000 ChIP-seq datasets for over 900 TFs for human and over 500 TFs for mouse to make accurate predictions. We demonstrate that BART outperforms existing methods in identifying the true TF from target gene sets. BART can be useful for any researcher in studying cancer gene regulation and cancer epigenetics, and demonstrates the power of utilizing public data for computational biology research. BART web server is freely available at: http://bartweb.org. Citation Format: Zhenjia Wang, Wenjing Ma, Yifan Zhang, Neal E. Magee, Yang Chen, Chongzhi Zang. BART: An integrative bioinformatics toolkit and web server for functional transcription factor prediction [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3214.

Epigenetics in Esophageal Cancer: From Mechanisms to Therapeutics

AbstractEsophageal 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 IA01: The epigenetics of cancer

Abstract Human cancers are initiated and maintained by DNA mutations and also by alterations in the cancer epigenome. The interaction between these processes is underscored by the observation that all human cancers contain DNA methylation aberrations and also frequently harbor mutations in genes that modify the epigenome. These include the enzymes that apply and remove methyl groups to and from cytosine, DNMT3A and TET2. Abnormal DNA cytosine methylation has received the most attention in our understanding of its potential to silence tumor suppressor genes and thus to directly contribute to the malignant phenotype. There are now many drugs that can target the epigenome, and I will focus on those that inhibit DNA methylation. It is important that we understand how these drugs elicit responses in patients, and most of the attention to date has centered on their ability to activate genes that are methylated and altered in a cancer relative to the normal tissue. However, a large percentage of the human genome codes for transposable elements, and these are often silenced by DNA methylation. Activation of these transposable elements can give rise to a state of “viral mimicry” in which a cancer cell behaves as though it is infected by an exogenous virus. I will explore how this activation of transposable elements may contribute to an interferon response that leads to apoptosis of cancer cells and to increased visibility to the immune system. Coupling epigenetic therapies with other approaches may be useful in the future in the treatment of cancers, including bladder cancer. Citation Format: Peter A. Jones. The epigenetics of cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA01.

Multi-faceted epigenetic dysregulation of gene expression promotes esophageal squamous cell carcinoma

Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to delineate the methylome landscape and characterize the oncogenic drivers of esophageal squamous cell carcinoma (ESCC). We found 98% of CpGs are hypomethylated across the ESCC genome. Hypo-methylated regions are enriched in areas with heterochromatin binding markers (H3K9me3, H3K27me3), while hyper-methylated regions are enriched in polycomb repressive complex (EZH2/SUZ12) recognizing regions. Altered methylation in promoters, enhancers, and gene bodies, as well as in polycomb repressive complex occupancy and CTCF binding sites are associated with cancer-specific gene dysregulation. Epigenetic-mediated activation of non-canonical WNT/β-catenin/MMP signaling and a YY1/lncRNA ESCCAL-1/ribosomal protein network are uncovered and validated as potential novel ESCC driver alterations. This study advances our understanding of how epigenetic landscapes shape cancer pathogenesis and provides a resource for biomarker and target discovery.

Review; Role of epigenetics in cancer

The epigenetic alterations are central to numerous human diseases, counting cancer. Typically, cancer has been seen as a hereditary infection, and it is presently getting to be clear that the onset of cancer is gone before by epigenetic anomalies. Examiners within the quickly growing field of epigenetics have recorded broad genomic reconstructing in cancer cells, counting methylation of deoxyribonucleic acid (DNA), chemical alteration of the histone proteins, and RNA-dependent control. Recognizing that carcinogenesis includes both hereditary and epigenetic alterations have driven to distant better an understanding of the molecular pathways that oversee the advancement of cancer and to changes in diagnosing and foreseeing the result of different sorts of cancer. Thinks about of the mechanism (s) of epigenetic control and its reversibility have brought about within the recognizable proof of novel targets which will be valuable in creating unused methodologies for the avoidance and treatment of cancer. Cancer is the appearance of both hereditary and epigenetic adjustments. In spite of the fact that cancer start and movement is overwhelmingly driven by procured hereditary modifications, it is getting to be clear that microenvironment mediated epigenetic annoyances play critical parts in neoplastic advancement. Epigenetics is characterized as heritable changes in quality expression, movement and expression that happen without change in DNA arrangements but which are adequately capable to control the flow of quality expression. The key forms that are mindful for epigenetic control are DNA methylation, adjustments in chromatin (covalent adjustment of center histones), nucleosome situating (physical modification), and post-transcriptional quality direction by noncoding RNA (micro-RNAs). A number of well characterized epigenetic adjustments are connected to distorted quality capacities and modified designs of quality expression that play basic parts within the patho-biology of cancer

SERS-Based Assessment of MRD in Acute Promyelocytic Leukemia?

Acute promyelocytic leukemia (APL) is characterized by a unique chromosome translocation t(15;17)(q24;q21), which leads to the PML/RARA gene fusion formation. However, it is acknowledged that this rearrangement alone is not able to induce the whole leukemic phenotype. In addition, epigenetic processes, such as DNA methylation, may play a crucial role in leukemia pathogenesis. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), involves the covalent transfer of a methyl group (-CH3) to the fifth carbon of the cytosine ring in the CpG dinucleotide and results in the formation of 5-methylcytosine (5-mC). The aberrant gene promoter methylation can be an alternative mechanism of tumor suppressor gene inactivation. Understanding cancer epigenetics and its pivotal role in oncogenesis, can offer us not only attractive targets for epigenetic treatment but can also provide powerful tools in monitoring the disease and estimating the prognosis. Several genes of interest, such as RARA, RARB, p15, p16, have been studied in APL and their methylation status was correlated with potential diagnostic and prognostic significance. In the present manuscript we comprehensively examine the current knowledge regarding DNA methylation in APL pathogenesis. We also discuss the perspectives of using the DNA methylation patterns as reliable biomarkers for measurable residual disease (MRD) monitoring and as a predictor of relapse. This work also highlights the possibility of detecting aberrant methylation profiles of circulating tumor DNA (ctDNA) through liquid biopsies, using the conventional methods, such as methylation-specific polymerase chain reaction (MS-PCR), sequencing methods, but also revolutionary methods, such as surface-enhanced Raman spectroscopy (SERS).

Visualizing Human Colorectal Cancer Intratumor Heterogeneity with Phylogeography.

Phylogeography combines ancestry with location and can be translated to intratumor heterogeneity (ITH) to visualize how tumors spread. ITH is common in human tumors, with many genetic and phenotypic differences between regions. The roles of ITH in progression are uncertain because many subclones lack discernable driver mutations. ITH can be visualized by mapping mutations onto microscopic sections, where subclones are directly associated with phenotypes, especially the deeper areas with the more invasive cells that confer worst clinical outcomes. Instead of a stepwise hierarchy where subclones segregate by phenotype with later branching subclones in more invasive areas, multiple subclones share superficial and invasive phenotype and are jigsaw arrayed in vertical columns. Phylogeography shows that both early and late subclones extend from the surface to the invasive front, suggesting that founder cells start with phenotypic plasticity and essentially all the drivers necessary to rapidly grow into large invasive tumors.

Overview on Epigenetics and Cancer

Epigenetics is considered as the science of hereditary phenotype which does not encompass amendment in the DNA. This occurs through chemical processes that modify the phenotype, without altering the genotype. A large number of studies showed that metabolic diseases are highly associated with epigenetic alterations suggesting that epigenetic factors may play a central role in cancer. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. Studies of the mechanism(s) of epigenetic regulation and its reversibility have resulted in the identification of novel targets that may be useful in developing new strategies for the prevention and treatment of cancer.

Cancer stem cells, epigenetics, tumor microenvironment and future therapeutics in cutaneous malignant melanoma: a review.

This review provides an overview of the current understanding of the ontogeny and biology of melanoma stem cells in cutaneous malignant melanoma. This article also summarizes and evaluates the current knowledge of the underlying epigenetic mechanisms, the regulation of melanoma progress by the tumor microenvironment as well as the therapeutic implications and applications of these novel insights, in the setting of personalized medicine. Unraveling the complex ecosystem of cutaneous malignant melanoma and the interplay between its components, aims to provide novel insights into the establishment of efficient therapeutic strategies.

Cancer Treatment: An Epigenetic View.

Cancer can be identified as an uncontrolled growth and reproduction of cell. Accumulation of genetic aberrations (mutations of oncogenes and tumor-suppressor genes and epigenetic modifications) is one of the characteristics of cancer cell. Increasing number of studies highlighted importance of the epigenetic alterations in cancer treatment and prognosis. Now, cancer epigenetics have a huge importance for developing novel biomarkers and therapeutic target for cancer. In this review, we will provide a summary of the major epigenetic changes involved in cancer and preclinical results of epigenetic therapeutics.