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Cell death is a fundamental part of life for metazoans. To maintain the balance between cell proliferation and metabolism of human bodies, a certain number of cells need to be removed regularly. Hence, the mechanisms of cell death have been preserved during the evolution of multicellular organisms. Tumorigenesis is closely related with exceptional inhibition of cell death. Mutations or defects in cell death-related genes block the elimination of abnormal cells and enhance the resistance of malignant cells to chemotherapy. Therefore, the investigation of cell death mechanisms enables the development of drugs that directly induce tumor cell death. In the guidelines updated by the Cell Death Nomenclature Committee (NCCD) in 2018, cell death was classified into 12 types according to morphological, biochemical and functional classification, including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, PARP-1 parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence and mitotic catastrophe. The mechanistic relationships between epigenetic controls and cell death in cancer progression were previously unclear. In this review, we will summarize the mechanisms of cell death pathways and corresponding epigenetic regulations. Also, we will explore the extensive interactions between these pathways and discuss the mechanisms of cell death in epigenetics which bring benefits to tumor therapy., Competing Interests: Declarations. Ethics approval and consent to participate: This study was conducted at the Xiangya Hospital, Central South University, Hunan, China. All of the protocols were reviewed and approved by the Joint Ethics Committee of the Central South University Health Authority and performed in accordance with national guidelines. Consent for publication: This manuscript has been read and approved by all the authors to publish and is not submitted or under consideration for publication elsewhere. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Tumor energy metabolism plays a crucial role in the occurrence, progression, and drug resistance of tumors. The study of tumor energy metabolism has gradually become an emerging field of tumor treatment. Recent studies have shown that epigenetic regulation is closely linked to tumor energy metabolism, influencing the metabolic remodeling and biological traits of tumor cells. This review focuses on the primary pathways of tumor energy metabolism and explores therapeutic strategies to target these pathways. It covers key areas such as glycolysis, the Warburg effect, mitochondrial function, oxidative phosphorylation, and the metabolic adaptability of tumors. Additionally, this article examines the role of the epigenetic regulator SWI/SNF complex in tumor metabolism, specifically its interactions with glucose, lipids, and amino acids. Summarizing therapeutic strategies aimed at these metabolic pathways, including inhibitors of glycolysis, mitochondrial-targeted drugs, exploitation of metabolic vulnerabilities, and recent developments related to SWI/SNF complexes as potential targets. The clinical significance, challenges, and future directions of tumor metabolism research are discussed, including strategies to overcome drug resistance, the potential of combination therapy, and the application of new technologies., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: The publication of the article was made by all authors. Competing interests: No potential conflict of interest was reported by the authors., (© 2024. The Author(s).)

Long non-coding RNAs (lncRNAs) have emerged as critical regulators of epigenome, modulating gene expression through DNA methylation, histone modification, and/or chromosome remodeling. Dysregulated lncRNAs act as oncogenes or tumor suppressors, driving tumor progression by shaping the cancer epigenome. By interacting with the writers, readers, and erasers of the epigenetic script, lncRNAs induce epigenetic modifications that bring about changes in cancer cell proliferation, apoptosis, epithelial-mesenchymal transition, migration, invasion, metastasis, cancer stemness and chemoresistance. This review analyzes and discusses the multifaceted role of lncRNAs in cancer pathobiology, from cancer genesis and progression through metastasis and therapy resistance. It also explores the therapeutic potential of targeting lncRNAs through innovative diagnostic, prognostic, and therapeutic strategies. Understanding the dynamic interplay between lncRNAs and epigenome is crucial for developing personalized therapeutic strategies, offering new avenues for precision cancer medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifying enzymes in pathological conditions. Over the past two decades, a growing array of small molecule drugs targeting epigenetic enzymes such as DNA methyltransferase, histone deacetylase, isocitrate dehydrogenase, and enhancer of zeste homolog 2, have been thoroughly investigated and implemented as therapeutic options, particularly in oncology. Additionally, numerous epigenetics-targeted drugs are undergoing clinical trials, offering promising prospects for clinical benefits. This review delineates the roles of epigenetics in physiological and pathological contexts and underscores pioneering studies on the discovery and clinical implementation of epigenetics-targeted drugs. These include inhibitors, agonists, degraders, and multitarget agents, aiming to identify practical challenges and promising avenues for future research. Ultimately, this review aims to deepen the understanding of epigenetics-oriented therapeutic strategies and their further application in clinical settings., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The association between increased cancer risk following a cerebrovascular event (CVE) has been previously reported. We hypothesize that biological age (B-age) acceleration is involved in this association. Our study aims to examine B-age as a novel contributing factor to cancer development post-CVE., Methods: From our prospective stroke registry (BasicMar), we selected 940 cases with epigenetic data. For this study, we specifically analyzed 648 of these patients who had available data, no prior history of cancer, and a minimum follow-up of 3 months. The primary outcome was cancer incidence. B-age was estimated using DNA methylation data derived from whole blood samples obtained within 24 h of stroke onset, employing various epigenetic clocks (including Hannum, Horvath, PhenoAge, Zhang BLUP , Zhang EN , and the mitotic epiTOC). Extrinsic epigenetic age acceleration (EEAA) was calculated as the residuals from the regression of B-age against chronological age (C-age). For epiTOC, the age-adjusted values were obtained by regressing out the effect of age from the raw epiTOC measurements. Estimated white cell counts were derived from DNA methylation data, and these cell fractions were used to compute the intrinsic epigenetic age acceleration (IEAA). Subsequently, we evaluated the independent association between EEAA, IEAA, and cancer incidence while controlling for potential confounding variables., Results: Among 648 patients with a median follow-up of 8.15 years, 83 (12.8%) developed cancer. Cox multivariable analyses indicated significant associations between Hannum, Zhang, and epiTOC EEAA and the risk of cancer after CVE. After adjusting for multiple testing and competing risks, EEAA measured by Hannum clock maintained an independent association with cancer risk. Specifically, for each year increase in Hannum's EEAA, we observed a 6.0% increased incidence of cancer (HR 1.06 [1.02-1.10], p value = 0.002)., Conclusions: Our findings suggest that epigenetic accelerated aging, as indicated by Hannum's EEAA, may play a significant role in the increased cancer risk observed in CVE survivors., Competing Interests: Declarations. Ethics approval and consent to participate: All the cohorts and samples involved in the study followed the national and international guidelines (Deontological Code, Declaration of Helsinki) and complied with the current personal data protection regulations, The Regulation (EU) 2016/679 of the European Parliament, and Ley Orgánica 3/2018 on protection of digital rights (LOPDPGDD). Local Institutional Review Boards approved all study aspects (CEIm-PSMAR, 2008/3083/l). Informed written consent was obtained from all patients or their relatives to be included in the study. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Cancer-associated fibroblasts (CAFs) are essential components of the tumor microenvironment and play a critical role in cancer progression. Numerous studies have identified significant molecular differences between CAFs and normal tissue-associated fibroblasts (NAFs). In this study, we isolated CAFs and NAFs from liver tumors and conducted a comprehensive analysis of their DNA methylation profiles, integrating our finding with data from studies on other cancer types., Results: Our analysis revealed that several CAF samples exhibited aberrant DNA methylation patterns, which corresponded with altered gene expression levels. Notably, DNA methylation at liver CAF-specific CpG sites was linked to survival outcomes in liver cancer datasets. An integrative analysis using publicly available datasets from various cancer types, including lung, prostate, esophageal, and gastric cancers, uncovered common epigenetic abnormalities across these cancers. Among the consistently altered CpGs were cg09809672 (EDARADD), cg07134930 (HDAC4), and cg05935904 (intergenic). These methylation changes were associated with prognosis across multiple cancer types., Conclusion: The activation of CAFs by the tumor microenvironment seems to be associated with distinct epigenetic modifications. Remarkably, similar genomic regions tend to undergo hypomethylation in CAFs across different studies and cancer types. Our findings suggest that CAF-associated DNA methylation changes hold potential as prognostic biomarkers. However, further research and validation are necessary to develop and apply such signatures in a clinical setting., Competing Interests: Declarations. Ethics approval and consent to participate: Liver biopsies were received from the Clinic for General, Visceral, Children and Transplantation Surgery at the University Hospital of RWTH Aachen after informed and written consent and following the guidelines of the Ethic Committee for the Use of Human Subjects at the University of Aachen (Permit number: EK 206/09). Consent for publication: Not applicable. Availability of data and materials: DNA methylation profiles generated in this study can be accessed from the Gene expression omnibus (GEO) under accession number GSE255123; the RNA-sequencing data are accessible under GSE255122. The following tokens have been created to allow review of the records GSE255123 (qxahsaionterlqr) and GSE255122 (khmjmegabnmjnqn). Competing interests: W.W. is involved in the company Cygenia GmbH ( www.cygenia.com ) that can provide service for epigenetic analysis to other scientists. Apart from this, the authors have no competing interests to declare., (© 2024. The Author(s).)

In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors. We perform a screen of human epigenetic regulators, identifying IKZF1 as a driver of T cell exhaustion. We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent T cell exhaustion., Competing Interests: Declaration of interests J.D.B. holds patents related to ATAC-seq and is an SAB member of Camp4 and seqWell. G.B., E.J., A.G., I.K.R., A.S.D., L.P., J.K., M.G.O., S.C., and D.A.M. are current or former employees of AstraZeneca. V.B.-W. is an employee of Revvity. S.L.T. was formerly an employee of Revvity., (Copyright © 2024. Published by Elsevier Inc.)

Epigenetic modifications and their alterations can cause variation in gene expression patterns which can ultimately affect a healthy individual. Until a few years ago, it was thought that the epigenome affects the transcriptome which can regulate the proteome and the metabolome. Recent studies have shown that the metabolome independently also plays a major role in regulating the epigenome bypassing the need for transcriptomic control. Alternatively, an imbalanced metabolome, stemming from transcriptome abnormalities, can further impact the transcriptome, creating a self-perpetuating cycle of interconnected occurrences. As a result, external factors such as nutrient intake and diet can have a direct impact on the metabolic pools and its reprogramming can change the levels and activity of epigenetic modifiers. Thus, the epigenetic landscape steers toward a diseased condition. In this review, we have discussed how different metabolites and dietary patterns can bring about changes in different arms of the epigenetic machinery such as methylation, acetylation as well as RNA mediated epigenetic mechanisms. We checked for limiting metabolites such as αKG, acetyl-CoA, ATP, NAD+, and FAD, whose abundance levels can lead to common diseases such as cancer, neurodegeneration etc. This gives a clearer picture of how an integrated approach including both epigenetics and metabolomics can be used for therapeutic purposes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Protein function alteration and protein mislocalization are cancer hallmarks that drive oncogenesis. N 6 -methyladenosine (m 6 A) deposition mediated by METTL3, METTL16, and METTL5 together with the contribution of additional subunits of the m 6 A system, has shown a dramatic impact on cancer development. However, the cellular localization of m 6 A proteins inside tumor cells has been little studied so far. Interestingly, recent evidence indicates that m 6 A methyltransferases are not always confined to the nucleus, suggesting that epitranscriptomic factors may also have multiple oncogenic roles beyond m 6 A that still represent an unexplored field. To date novel epigenetic drugs targeting m 6 A modifiers, such as METTL3 inhibitors, are entering into clinical trials, therefore, the study of the potential onco-properties of m 6 A effectors beyond m 6 A is required. Here we will provide an overview of methylation-independent functions of the m 6 A players in cancer, describing the molecular mechanisms involved and the future implications for therapeutics., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical pathway in cancer biology. This review delves into the epigenetic mechanisms that modulate ferroptosis in cancer cells, focusing on how DNA methylation, histone modifications, and non-coding RNAs influence the expression and function of essential genes involved in this process. By unraveling the complex interplay between these epigenetic mechanisms and ferroptosis, the article sheds light on novel gene targets and functional insights that could pave the way for innovative cancer treatments to enhance therapeutic efficacy and overcome resistance in cancer therapy.

In recent years, significant strides in both conceptual understanding and technological capabilities have bolstered our comprehension of the factors underpinning cancer initiation and progression. While substantial insights have unraveled the molecular mechanisms driving carcinogenesis, there has been an overshadowing of the critical contribution made by epigenetic pathways, which works in concert with genetics. Mounting evidence demonstrates cancer as a complex interplay between genetics and epigenetics. Notably, epigenetic elements play a pivotal role in governing alternative pre-mRNA splicing, a primary contributor to protein diversity. In this review, we have provided detailed insights into the bidirectional communication between epigenetic modifiers and alternative splicing, providing examples of specific genes and isoforms affected. Notably, succinct discussion on targeting epigenetic regulators and the potential of the emerging field of epigenome editing to modulate splicing patterns is also presented. In summary, this review offers valuable insights into the intricate interplay between epigenetics and alternative splicing in cancer, paving the way for novel approaches to understanding and targeting this critical process., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Emerging evidence indicates that metabolism not only is a source of energy and biomaterials for cell division but also acts as a driver of cancer cell plasticity and treatment resistance. This is because metabolic changes lead to remodeling of chromatin and reprogramming of gene expression patterns, furthering tumor cell phenotypic transitions. Therefore, the crosstalk between metabolism and epigenetics seems to hold immense potential for the discovery of novel therapeutic targets for various aggressive tumors. Here, we highlight recent discoveries supporting the concept that the cooperation between metabolism and epigenetics enables cancer to overcome mounting treatment-induced pressures. We discuss how specific metabolites contribute to cancer cell resilience and provide perspective on how simultaneously targeting these key forces could produce synergistic therapeutic effects to improve treatment outcomes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cancer stem cells (CSCs) are a poorly differentiated population of malignant cells that (at least in some neoplasms) is responsible for tumor progression, resistance to therapy, and disease relapse. According to a widely accepted model, all stages of cancer progression involve the ability of neoplastic cells to evade recognition or elimination by the host immune system. In line with this notion, CSCs are not only able to cope with environmental and therapy-elicited stress better than their more differentiated counterparts but also appear to better evade tumor-targeting immune responses. We summarize epigenetic modifications of DNA and histones through which CSCs evade immune recognition or elimination, and propose that such alterations constitute promising therapeutic targets to increase the sensitivity of some malignancies to immunotherapy., Competing Interests: Declaration of interests ME is/has been holding research contracts with Ferrer International and Incyte, and receives personal fees from Quimatryx (outside the scope of this work). LG is/has been holding research contracts with Lytix Biopharma, Promontory, and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation, and holds Promontory stock options (outside the scope of this work). The other authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dynamic alterations in cellular phenotypes during cancer progression are attributed to a phenomenon known as 'lineage plasticity'. This process is associated with therapeutic resistance and involves concurrent shifts in metabolic states that facilitate adaptation to various stressors inherent in malignant growth. Certain metabolites also serve as synthetic reservoirs for chromatin modification, thus linking metabolic states with epigenetic regulation. There remains a critical need to understand the mechanisms that converge on lineage plasticity and metabolic reprogramming to prevent the emergence of lethal disease. This review attempts to offer an overview of our current understanding of the interplay between metabolic reprogramming and lineage plasticity in the context of cancer, highlighting the intersecting drivers of cancer hallmarks, with an emphasis on solid tumors., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Human endogenous retroviruses (HERVs), integrated into the human genome during primate evolution, constitute approximately 8% of the human genome. Although most HERVs are non-protein-coding owing to mutations, insertions, deletions, and truncations, recent research has revealed their diverse roles in biological processes, including disease pathogenesis., Objective: Although many HERVs remain inactive, they have been implicated in various diseases, particularly cancer, prompting an increased interest in harnessing HERVs for therapeutic purposes. This review explores the recent advancements in our understanding of the biological roles of HERVs, emphasizing their clinical relevance in cancer treatment., Methods: Here, we discuss how the detection of transposable elements (TEs), including HERVs, by the immune system triggers innate immune responses in human cancers., Conclusion: Additionally, we outline recent progress in elucidating the implications of HERV activation in cancer and how targeting HERVs holds promise for anti-cancer treatments by modulating epigenetic plasticity and disrupting cancer initiation and progression., Competing Interests: Declarations. Ethical approval: Not applicable. Informed consent: Not applicable. Conflict of interest: The authors declare that they have no conflict of interest., (© 2024. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Epigenetic dysregulation has long been recognized as a significant contributor to tumorigenesis and tumor maintenance, impacting all recognized cancer hallmarks. Although some epigenetic drugs have received regulatory approval for certain hematological malignancies, their efficacy in treating solid tumors has so far been largely disappointing. However, recent advancements in developing new compounds and a deeper understanding of cancer biology have led to success in specific solid tumor subtypes through precision medicine approaches. Moreover, epigenetic drugs may play a crucial role in synergizing with other anticancer treatments, enhancing the sensitivity of cancer cells to various anticancer therapies, including chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy. In this review, we critically evaluate the evolution of epigenetic drugs, tracing their development from initial use as monotherapies to their current application in combination therapies. We explore the preclinical rationale, completed clinical studies, and ongoing clinical trials. Finally, we discuss trial design strategies and drug scheduling to optimize the development of possible combination therapies., Competing Interests: MM reports honoraria from AstraZeneca (

The interplay between cancer and the immune system has captivated researchers for a long time. Recent developments in cancer immunotherapy have substantiated this interest with a significant benefit to cancer patients. Tumor and immune cells are regulated via a wide range of molecular mechanisms involving intricate transcriptional and epigenetic networks. Epigenetic processes influence chromatin structure and accessibility, thus governing gene expression, replication, and DNA damage repair. However, aberrations within epigenetic signatures are frequently observed in cancer. One of the key epigenetic marks is the trimethylation of histone 3 at lysine 9 (H3K9me3), confined mainly within constitutive heterochromatin to suppress DNA accessibility. It is deposited at repetitive elements, centromeric and telomeric loci, as well as at the promoters of various genes. Dysregulated H3K9me3 deposition disrupts multiple pathways, including immune signaling. Consequently, altered H3K9me3 dynamics may modify the efficacy of immunotherapy. Indeed, growing evidence highlights the pivotal roles of various proteins mediating H3K9me3 deposition (SETDB1/2, SUV39H1/2), erasure (KDM3, KDM4 families, KDM7B, LSD1) and interpretation (HP1 proteins, KAP1, CHD4, CDYL, UHRF1) in modulating immunotherapy effectiveness. Here, we review the existing literature to synthesize the available information on the influence of these H3K9me3 writers, erasers, and readers on the response to immunotherapy.

The catalytic activity of most epigenetic enzymes requires a metabolite produced by central carbon metabolism as a cofactor or (co-)substrate. The concentrations of these metabolites undergo dynamic changes in response to nutrient levels and environmental conditions, reprogramming metabolic processes and epigenetic landscapes. Abnormal accumulations of epigenetic modulatory metabolites resulting from mutations in metabolic enzymes contribute to tumorigenesis. In this review, we first present the concept that metabolite regulation of gene expression represents an evolutionarily conserved mechanism from prokaryotes to eukaryotes. We then review how individual metabolites affect epigenetic enzymes and cancer development. Lastly, we discuss the advancement of and opportunity for therapeutic targeting of metabolite-epigenetic regulation in cancer therapy., Competing Interests: Declaration of interests Y.X. is an employee of Cullgen, Inc., and equity holder of Cullgen, Inc., and Meton Biopharma., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cancer has arisen from both genetic mutations and epigenetic changes, making epigenetics a crucial area of research for innovative cancer prevention and treatment strategies. This dual perspective has propelled epigenetics into the forefront of cancer research. This review highlights the important roles of DNA methylation, histone modifications and non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs, which are key regulators of cancer-related gene expression. It explores the potential of epigenetic-based therapies to revolutionize patient outcomes by selectively modulating specific epigenetic markers involved in tumorigenesis. The review examines promising epigenetic biomarkers for early cancer detection and prognosis. It also highlights recent progress in oligonucleotide-based therapies, including antisense oligonucleotides (ASOs) and antimiRs, to precisely modulate epigenetic processes. Furthermore, the concept of epigenetic editing is discussed, providing insight into the future role of precision medicine for cancer patients. The integration of nanomedicine into cancer therapy has been explored and offers innovative approaches to improve therapeutic efficacy. This comprehensive review of recent advances in epigenetic-based cancer therapy seeks to advance the field of precision oncology, ultimately culminating in improved patient outcomes in the fight against cancer., (© 2024. The Author(s).)

As epigenetic therapies continue to gain ground as potential treatment strategies for cancer and other diseases, compounds that target histone lysine methylation and the enzyme complexes represent a major frontier for therapeutic development. Clinically viable therapies targeting the activities of histone lysine methyltransferases (HKMT) and demethylases (HKDMs) have only recently begun to emerge following FDA approval of the EZH2 inhibitor tazemetostat in 2020 and remain limited to compounds targeting the well-studied SET domain-containing HKMTs and their opposing HKDMs. These include the H3K27 methyltransferases EZH2/EZH1, the singular H3K79 methyltransferase DOT1L, and the H3K4 methyltransferase MLL1/COMPASS as well as H3K9 and H3K36 methyltransferases. They additionally include the H3K4/9-preferential demethylase LSD1 and the H3K4-, H3K27-, and H3K36-preferential KDM5, KDM6, and KDM2 demethylase subfamilies, respectively. This Review discusses the results of recent clinical and preclinical studies relevant to all of these existing and potential therapies. It provides an update on advancements in therapeutic development, as well as more basic molecular understanding, within the past 5 years approximately. It also offers a perspective on histone lysine methylation that departs from the long-predominant "histone code" metaphor, emphasizing complex-disrupting inhibitors and proximity-based approaches rather than catalytic domain inhibitors in the outlook for future therapeutic development.

Sirtuins (SIRTs) are well-known as nicotinic adenine dinucleotide + (NAD + )-dependent histone deacetylases, which are important epigenetic enzymes consisting of seven family members (SIRT1-7). Of note, SIRT1 and SIRT2 are distributed in the nucleus and cytoplasm, while SIRT3, SIRT4 and SIRT5 are localized in the mitochondria. SIRT6 and SIRT7 are distributed in the nucleus. SIRTs catalyze the deacetylation of various substrate proteins, thereby modulating numerous biological processes, including transcription, DNA repair and genome stability, metabolism, and signal transduction. Notably, accumulating evidence has recently underscored the multi-faceted roles of SIRTs in both the suppression and progression of various types of human cancers. Crucially, SIRTs have been emerging as promising therapeutic targets for cancer therapy. Thus, in this review, we not only present an overview of the molecular structure and function of SIRTs, but elucidate their intricate associations with oncogenesis. Additionally, we discuss the current landscape of small-molecule activators and inhibitors targeting SIRTs in the contexts of cancer and further elaborate their combination therapies, especially highlighting their prospective utility for future cancer drug development., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, in the latest iteration of the cancer hallmarks, "nonmutational epigenetic reprogramming" was newly added. However, epigenetics, much like genetics, is a broad scientific area that deserves further attention due to its multiple roles in cancer initiation, progression, and adaptive nature. Herein, we present a detailed examination of the epigenetic hallmarks affected in human cancer, elucidating the pathways and genes involved, and dissecting the disrupted landscapes for DNA methylation, histone modifications, and chromatin architecture that define the disease. Significance: Cancer is a disease characterized by constant evolution, spanning from its initial premalignant stages to the advanced invasive and disseminated stages. It is a pathology that is able to adapt and survive amidst hostile cellular microenvironments and diverse treatments implemented by medical professionals. The more fixed setup of the genetic structure cannot fully provide transformed cells with the tools to survive but the rapid and plastic nature of epigenetic changes is ready for the task. This review summarizes the epigenetic hallmarks that define the ecological success of cancer cells in our bodies., (©2024 American Association for Cancer Research.)

Limited CAR T-cell expansion and persistence hinder therapeutic responses in solid cancer patients. To enhance the functional persistence of engineered T-cell therapies, we performed genetic disruption in human CAR T cells of SUV39H1, a histone 3 lysine 9 methyltransferase that promotes heterochromatin formation. This resulted in phenotypic CAR-T reprogramming that elicited optimal and sustained antitumor functionality. Single-cell transcriptomic (scRNA-seq) and chromatin accessibility (scATAC-seq) analyses of tumor-infiltrating CAR T cells showed early reprogramming into self-renewing, stem-like populations with decreased expression of dysfunction genes in all subpopulations. Moreover, we provided evidence that SUV39H1 inactivation elicits potent and durable functional persistence upon multiple tumor rechallenges. This opens a safe path to enhancing adoptive cell therapies for solid tumors., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The traditional view of cancer emphasizes a genes-first process. Novel cancer traits arise by genetic mutations that spread to drive phenotypic change. However, recent data support a phenotypes-first process in which nonheritable cellular variability creates novel traits that later become heritably stabilized by genetic and epigenetic changes. Single-cell measurements reinforce the idea that phenotypes lead genotypes, showing how cancer evolution follows normal developmental plasticity and creates novel traits by recombining parts of different cellular developmental programs. In parallel, studies in evolutionary biology also support a phenotypes-first process driven by developmental plasticity and developmental recombination. These advances in cancer research and evolutionary biology mutually reinforce a revolution in our understanding of how cells and organisms evolve novel traits in response to environmental challenges., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cancer hypoxia, a crucial characteristic of malignancy, ranging from practically non-hypoxic to severe, impacts gene expression, metabolism and mechanisms associated with tumor formation serves as a key obstacle in cancer therapy. It triggers a complex network of cell signaling pathways, such as the NF-κB, PI3K, mTOR/AKT,MAPK, HIF and their associated genes regulating the effects of the same. The onset and advancement of cancer are attributed to genetic and epigenetic modifications which are intrinsically related. Off late, it has been observed that in disease progression, the epigenetic modifications lead to gene mutations that in turn alter the epigenome, presenting a major hurdle in fabricating treatment strategies. However, theprogress in science and technology has led to the emergence of various surfacing omics and multi-view clustering algorithms, which offer unparalleled prospects for further subtyping cancers, enhancing the prognosis and treatment results of these subtypes, and comprehending crucial pathophysiological mechanisms across diverse molecular strata. Multi-omics has allowed scientists to gain a more comprehensive understanding of the various ways that cellular malfunction can lead to cancer. So, it becomes of utmost importance to firstly understand the epigenetic changes taking place in tumor hypoxia at gene level. This review sheds light on the role of HIF gene in hypoxic milieu and its relationship with mechanisms of cancer epigenetics. It further glances as to how omics approach can be used to study the oncogenic cellular changes and how bioinformatic tools aid in identification of complex gene networks involved in disease progression. Lastly, it glimpses through the benefits and shortcomings of the existing epi drug therapy and how it can be used in developing novel treatment options., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Of the seven in absentia homologue (SIAH) family, three members have been identified in the human genome. In contrast to the E3 ubiquitin ligase encoding SIAH1 and SIAH2, little is known on the regulation and function of SIAH3 in tumorigenesis. In this study, we reveal that SIAH3 is frequently epigenetically silenced in different cancer entities, including cutaneous melanoma, lung adenocarcinoma and head and neck cancer. Low SIAH3 levels correlate with an impaired survival of cancer patients. Additionally, induced expression of SIAH3 reduces cell proliferation and induces cell death. Functionally, SIAH3 negatively affects cellular metabolism by shifting cells form aerobic oxidative phosphorylation to glycolysis. SIAH3 is localized in the mitochondrion and interacts with proteins involved in mitochondrial ribosome biogenesis and translation. We also report that SIAH3 interacts with ubiquitin ligases, including SIAH1 or SIAH2, and is degraded by them. These results suggest that SIAH3 acts as an epigenetically controlled tumor suppressor by regulating cellular metabolism through the inhibition of oxidative phosphorylation., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Cancer, a complex and multifaceted group of diseases, continues to challenge the boundaries of medical science and healthcare. Its relentless impact on global health, both in terms of prevalence and mortality, underscores the urgent need for a comprehensive understanding of its underlying mechanisms and innovative therapeutic approaches. In recent years, significant progress has been achieved in identifying the genetic and epigenetic mechanisms that cause cancer development and treatment resistance. Researchers are currently investigating the possibility of epigenetic editing such as CRISPR-dCas9 (Clustered Regularly Interspaced Short Palindromic Repeats/deactivated CRISPR-associated protein 9) technologies, for targeting and modifying cancer related epigenetic alterations. A revolutionary form of precision cancer treatment called CRISPR-dCas9 is derived from the bacterial CRISPR-Cas (CRISPR-associated nuclease) system. CRISPR-dCas9 can be combined with epigenetic effectors (EE) to alter malignant epigenetic characteristics associated with cancer. The purpose of this review article is to provide a thorough analysis of recent advancements in utilizing CRISPR-dCas9 technology to target and modify epigenetic changes associated with cancer. This review aims to summarize the latest research developments, evaluate the effectiveness and limitations of CRISPR-dCas9 applications in cancer therapy, identify key challenges such as delivery methods and explore future directions for improving and expanding these technologies. Here, we address the various obstacles that may arise in clinical applications while showcasing the latest advancements and potential future uses of CRISPR-Cas9 in cancer therapy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Histone post-translational modifications (HPTMs), as one of the core mechanisms of epigenetic regulation, are garnering increasing attention due to their close association with the onset and progression of diseases and their potential as targeted therapeutic agents. Advances in high-throughput molecular tools and the abundance of bioinformatics data have led to the discovery of novel HPTMs which similarly affect gene expression, metabolism, and chromatin structure. Furthermore, a growing body of research has demonstrated that novel histone modifications also play crucial roles in the development and progression of various diseases, including various cancers, cardiovascular diseases, infectious diseases, psychiatric disorders, and reproductive system diseases. This review defines nine novel histone modifications: lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, and 2-hydroxybutyrylation. It comprehensively introduces the modification processes of these nine novel HPTMs, their roles in transcription, replication, DNA repair and recombination, metabolism, and chromatin structure, as well as their involvement in promoting the occurrence and development of various diseases and their clinical applications as therapeutic targets and potential biomarkers. Moreover, this review provides a detailed overview of novel HPTM inhibitors targeting various targets and their emerging strategies in the treatment of multiple diseases while offering insights into their future development prospects and challenges. Additionally, we briefly introduce novel epigenetic research techniques and their applications in the field of novel HPTM research., (© 2024. The Author(s).)

Although cancer immunotherapy has become a successful therapeutic strategy in a certain range of solid cancer and hematological malignancies, this efficacy of immunotherapy is impeded by limited success rates due to an immunologically "cold" state. The cGAS-STING signaling pathway is an evolutionarily conserved system which can find cytoplasmic DNA to regulate the innate immune and adaptive immune response. Beyond the host defense and autoimmune disorders, recent advances have now expanded the roles of cGAS-STING that is precise activated and tight regulated to improve anticancer immunity. Mounting evidence now has shown the crucial role of epigenetic regulation in mediating the expression of key genes associated with the cGAS-STING signaling pathway. In this review, we highlight the structure and cellular localization of cGAS and STING as well as intracellular cascade reaction of cGAS-STING signal transduction. We further summarize recent findings of epigenetic regulatory mechanisms that control the expression of cGAS and STING in cancer. The review aims to offer theoretical basis and reference for targeting the epigenetic mechanisms that control cGAS and STING gene expression to promote the development of more effective combination therapeutic regimens to enhance the efficacy of cancer immunotherapy in clinical practice and cancer clinical and cancer research workers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Cancer remains a global health burden, shaped by both genetic mutations and epigenetic dysregulation. Epigenetic alteration plays a pivotal role in tumorigenesis, immune response modulation, and the emergence of treatment resistance. This review emphasizes the intricate interplay between epigenetically reprogrammed cancer cells and the tumor microenvironment (TME), a relationship central to the immunoediting concept, which encompasses elimination, equilibrium, and escape phases. This review highlights the significance of CD8 + T cells as potent anticancer agents and discusses the mechanisms by which tumor cells evade immune surveillance and evolve resistance to immunotherapy. Such evasion entails the regulation of inhibitory molecules, antigen presentation machinery, and cytokine milieu. Furthermore, this review explores the complex dynamics culminating in CD8 + T cell dysfunction within the TME. In summary, this work offers insights into the indispensable role of epigenetic mechanisms in bolstering cancer cell survival amidst immunological challenges within the TME., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Cellular crosstalk mediated by ligand-receptor interactions largely complicates the tumour ecosystem, resulting in heterogeneous tumour microenvironments that affect immune response and clinical benefits from immunotherapy. Epigenetic mechanisms are pivotal to expression changes of immune-related genes and can modulate the anti-tumour immune response. However, the functional consequences of disrupted epigenetic regulators (ERs) on ligand-receptor interactions in the tumour microenvironment remain largely unexplored. Here, we proposed mutations of ERs in perturbed interactions (MERIN), a molecular network-based approach that incorporates multi-omics data, to infer the potential consequences of ER mutations on ligand-receptor interaction perturbations. Leveraging cancer genomic profiles and molecular interaction data, we comprehensively decoded the functional consequences of ER mutations on dysregulated ligand-receptor interactions across 33 cancers. The dysregulated ligand-receptor genes were indeed enriched in cancer and immune-related function. We demonstrated the potential significance of PD1-PDL1 interaction-related ER mutations in stratifying cancer patients from multiple independent data cohorts. The ER mutation group showed distinct immunological characterizations and prognoses. Furthermore, we highlighted that the ER mutations could potentially predict clinical outcomes of immunotherapy. Our computational and clinical assessment underscore the utility of MERIN for elucidating the functional relevance of ER mutations in cancer immune response, potentially aiding patients' stratification for immunotherapy., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Abstract: Cancer development takes 10 to 50 years, and epigenetics plays an important role. Recent evidence suggests that ~80% of human cancers are linked to environmental factors impinging upon genetics/epigenetics. Because advanced metastasized cancers are resistant to radiation/chemotherapeutic drugs, cancer prevention by relatively nontoxic "epigenetic modifiers" will be logical. Many dietary phytochemicals possess powerful antioxidant and anti-inflammatory properties that are hallmarks of cancer prevention. Dietary phytochemicals can regulate gene expression of the cellular genome via epigenetic mechanisms. In this review, we will summarize preclinical studies that demonstrate epigenetic mechanisms of dietary phytochemicals in skin, colorectal, and prostate cancer prevention. Key examples of the importance of epigenetic regulation in carcinogenesis include hypermethylation of the NRF2 promoter region in cancer cells, resulting in inhibition of NRF2-ARE signaling. Many dietary phytochemicals demethylate NRF2 promoter region and restore NRF2 signaling. Phytochemicals can also inhibit inflammatory responses via hypermethylation of inflammation-relevant genes to block gene expression. Altogether, dietary phytochemicals are excellent candidates for cancer prevention due to their low toxicity, potent antioxidant and anti-inflammatory properties, and powerful epigenetic effects in reversing procarcinogenic events., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. This work was supported in part by institutional funds and by R01 AT009152 from the National Center for Complementary and Integrative Health, R01 CA200129 from the National Cancer Institute, and P30 ES005022 from the National Institute of Environmental Health., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Cancer is a highly heterogeneous disease, where phenotypically distinct subpopulations coexist and can be primed to different fates. Both genetic and epigenetic factors may drive cancer evolution, however little is known about whether and how such a process is pre-encoded in cancer clones. Using single-cell multi-omic lineage tracing and phenotypic assays, we investigate the predictive features of either tumour initiation or drug tolerance within the same cancer population. Clones primed to tumour initiation in vivo display two distinct transcriptional states at baseline. Remarkably, these states share a distinctive DNA accessibility profile, highlighting an epigenetic basis for tumour initiation. The drug tolerant niche is also largely pre-encoded, but only partially overlaps the tumour-initiating one and evolves following two genetically and transcriptionally distinct trajectories. Our study highlights coexisting genetic, epigenetic and transcriptional determinants of cancer evolution, unravelling the molecular complexity of pre-encoded tumour phenotypes., (© 2024. The Author(s).)

Indeed, tumors are a significant health concern worldwide, and understanding the underlying mechanisms of tumor development is crucial for effective prevention and treatment. Epigenetics, which refers to changes in gene expression that are not caused by alterations in the DNA sequence itself, plays a critical role in the entire process of tumor development. It goes without saying that the effect of methylation on tumors is a significant aspect of epigenetics. Among the methylation modifications, DNA methylation is an important part, which plays a regulatory role in tumor-related genes. Ten-eleven translocation 2 (TET2) is a highly influential protein involved in the modification of DNA methylation. Its primary role is associated with the suppression of tumor development, making it a significant player in cancer research. However, TET2 is frequently mentioned in hematological diseases, its role in solid tumors has received little attention. Studying the changes of TET2 in solid tumors and the regulatory mechanism will facilitate its investigation as a clinical target for targeted therapy and may also provide directions for clinical treatment of malignant tumors., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Transglutaminase 2 (TGM2) has been known as a well-characterized factor regulating the progression of multiple types of cancer, due to its multifunctional activities and the ubiquitous signaling pathways it is involved in. As a member of the transglutaminase family, TGM2 catalyzes protein post-translational modifications (PTMs), including monoaminylation, amide hydrolysis, cross-linking, etc., through the transamidation of variant glutamine-containing protein substrates. Recent discoveries revealed histone as an important category of TGM2 substrates, thus identifying histone monoaminylation as an emerging epigenetic mark, which is highly enriched in cancer cells and possesses significant regulatory functions of gene transcription. In this review, we will summarize recent advances in TGM2-mediated histone monoaminylation as well as its role in cancer and discuss the key research methodologies to better understand this unique epigenetic mark, thereby shedding light on the therapeutic potential of TGM2 as a druggable target in cancer treatment., (© 2024 The Author(s).)

Histones are the main components of chromatin, functioning as an instructive scaffold to maintain chromosome structure and regulate gene expression. The dysregulation of histone modification is associated with various pathological processes, especially cancer initiation and development, and histone methylation plays a critical role. However, the specific mechanisms and potential therapeutic targets of histone methylation in cancer are not elucidated. Lys-specific demethylase 1A (LSD1) was the first identified demethylase that specifically removes methyl groups from histone 3 at lysine 4 or lysine 9, acting as a repressor or activator of gene expression. Recent studies have shown that LSD1 promotes cancer progression in multiple epigenetic regulation or non-epigenetic manners. Notably, LSD1 dysfunction is correlated with repressive cancer immunity. Many LSD1 inhibitors have been developed and clinical trials are exploring their efficacy in monotherapy, or combined with other therapies. In this review, we summarize the oncogenic mechanisms of LSD1 and the current applications of LSD1 inhibitors. We highlight that LSD1 is a promising target for cancer treatment. This review will provide the latest theoretical references for further understanding the research progress of oncology and epigenetics, deepening the updated appreciation of epigenetics in cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The development of drug resistance remains a major challenge in cancer treatment. Ferroptosis, a unique type of regulated cell death, plays a pivotal role in inhibiting tumour growth, presenting new opportunities in treating chemotherapeutic resistance. Accumulating studies indicate that epigenetic modifications by non-coding RNAs (ncRNA) can determine cancer cell vulnerability to ferroptosis. In this review, we first summarize the role of chemotherapeutic resistance in cancer growth/development. Then, we summarize the core molecular mechanisms of ferroptosis, its upstream epigenetic regulation, and its downstream effects on chemotherapeutic resistance. Finally, we review recent advances in understanding how ncRNAs regulate ferroptosis and from such modulate chemotherapeutic resistance. This review aims to enhance general understanding of the ncRNA-mediated epigenetic regulatory mechanisms which modulate ferroptosis, highlighting the ncRNA-ferroptosis axis as a key druggable target in overcoming chemotherapeutic resistance., (© 2024. The Author(s).)

Epithelial-mesenchymal transition (EMT) is a process in which an epithelial cell undergoes multiple modifications, acquiring both morphological and functional characteristics of a mesenchymal cell. This dynamic process is initiated by various inducing signals that activate numerous signaling pathways, leading to the stimulation of transcription factors. EMT plays a significant role in cancer progression, such as metastasis and tumor heterogeneity, as well as in drug resistance. In this article, we studied molecular mechanisms, epigenetic regulation, and cellular plasticity of EMT, as well as microenvironmental factors influencing this process. We included both in vivo and in vitro models in EMT investigation and clinical implications of EMT, such as the use of EMT in curing oncological patients and targeting its use in therapies. Additionally, this review concludes with future directions and challenges in the wide field of EMT.

Epigenetic regulation, which is characterized by reversible and heritable genetic alterations without changing DNA sequences, has recently been increasingly studied in diseases. Histone variant regulation is an essential component of epigenetic regulation. The substitution of canonical histones by histone variants profoundly alters the local chromatin structure and modulates DNA accessibility to regulatory factors, thereby exerting a pivotal influence on gene regulation and DNA damage repair. Histone H2A variants, mainly including H2A.Z, H2A.B, macroH2A, and H2A.X, are the most abundant identified variants among all histone variants with the greatest sequence diversity. Harboring varied chromatin occupancy and structures, histone H2A variants perform distinct functions in gene transcription and DNA damage repair. They are implicated in multiple pathophysiological mechanisms and the emergence of different illnesses. Cancer, embryonic development abnormalities, neurological diseases, metabolic diseases, and heart diseases have all been linked to histone H2A variant alterations. This review focuses on the functions of H2A histone variants in mammals, including H2A.Z, H2A.B, macroH2A, and H2A.X, and their current roles in various diseases.

In cancer, synthetic lethality refers to the drug-induced inactivation of one gene and the inhibition of another in cancer cells by a drug, resulting in the death of only cancer cells; however, this effect is not present in normal cells, leading to targeted killing of cancer cells. Recent intensive epigenetic research has revealed that aberrant epigenetic changes are more frequently observed than gene mutations in certain cancers. Recently, numerous studies have reported various methylation synthetic lethal combinations involving DNA damage repair genes, metabolic pathway genes, and paralogs with significant results in cellular models, some of which have already entered clinical trials with promising results. This review systematically introduces the advantages of methylation synthetic lethality and describes the lethal mechanisms of methylation synthetic lethal combinations that have recently demonstrated success in cellular models. Furthermore, we discuss the future opportunities and challenges of methylation synthetic lethality in targeted anticancer therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer is the second leading cause of death worldwide and disease burden is expected to increase globally throughout the next several decades, with the majority of cancer-related deaths occurring in metastatic disease. Cancers exhibit known hallmarks that endow them with increased survival and proliferative capacities, frequently as a result of de-stabilizing mutations. However, the genomic features that resolve metastatic clones from primary tumors are not yet well-characterized, as no mutational landscape has been identified as predictive of metastasis. Further, many cancers exhibit no known mutation signature. This suggests a larger role for non-mutational genome re-organization in promoting cancer evolution and dissemination. In this review, we highlight current critical needs for understanding cell state transitions and clonal selection advantages for metastatic cancer cells. We examine links between epigenetic states, genome structure, and misregulation of tumor suppressors and oncogenes, and discuss how recent technologies for understanding domain-scale regulation have been leveraged for a more complete picture of oncogenic and metastatic potential., (© 2024. The Author(s).)

Metastasis is the primary cause of cancer-related death, with the dissemination and colonization of primary tumor cells at the metastatic site facilitated by various molecules and complex pathways. Understanding the biological mechanisms underlying the metastatic process is critical for the development of effective interventions. Several epigenetic modifications have been identified that play critical roles in regulating cancer metastasis. This review aims to provide a comprehensive summary of recent advances in understanding the role of epigenetic modifiers, including histone modifications, DNA methylation, non-coding RNAs, enhancer reprogramming, chromatin accessibility, and N6-methyladenosine, in metastasis-associated processes, such as epithelial-mesenchymal transition (EMT), cancer cell migration, and invasion. In particular, this review provides a detailed and in-depth description of the role of crosstalk between epigenetic regulators in tumor metastasis. Additionally, we explored the potential and limitations of epigenetics-related target molecules in the diagnosis, treatment, and prognosis of cancer metastasis.

Cancer treatment has always been a challenge for humanity. The inadequacies of current technologies underscore the limitations of our efforts against this disease. Nevertheless, the advent of targeted therapy has introduced a promising avenue, furnishing us with more efficacious tools. Consequently, researchers have turned their attention toward epigenetics, offering a novel perspective in this realm. The investigation of epigenetics has brought RNA readers to the forefront, as they play pivotal roles in recognizing and regulating RNA functions. Recently, the development of inhibitors targeting these RNA readers has emerged as a focal point in research and holds promise for further strides in targeted therapy. In this review, we comprehensively summarize various types of inhibitors targeting RNA readers, including non-coding RNA (ncRNA) inhibitors, small-molecule inhibitors, and other potential inhibitors. We systematically elucidate their mechanisms in suppressing cancer progression by inhibiting readers, aiming to present inhibitors of readers at the current stage and provide more insights into the development of anticancer drugs.

Epigenetic regulation of gene expression, without altering the DNA sequence, is involved in many normal cellular growth and division events, as well as diseases such as cancer. Epigenetics is no longer limited to DNA methylation, and histone modification, but regulatory non-coding RNAs (ncRNAs) also play an important role in epigenetics. Circular RNAs (circRNAs), single-stranded RNAs without 3' and 5' ends, have recently emerged as a class of ncRNAs that regulate gene expression. CircRNAs regulate phosphatase and tensin homolog (PTEN) expression at various levels of transcription, post-transcription, translation, and post-translation under their own regulation. Given the importance of PTEN as a tumor suppressor in cancer that inhibits one of the most important cancer pathways PI3K/AKT involved in tumor cell proliferation and survival, significant studies have been conducted on the regulatory role of circRNAs in relation to PTEN. These studies will be reviewed in this paper to better understand the function of this protein in cancer and explore new therapeutic approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dysregulation of histone deacetylases (HDACs) is closely associated with cancer development and progression. Here, we comprehensively analyzed the association between all HDAC family members and several clinicopathological and molecular traits of solid tumors across 22 distinct tumor types, focusing primarily on cancer stemness and immunity. To this end, we used publicly available TCGA data and several bioinformatic tools (i.e., GEPIA2, TISIDB, GSCA, Enrichr, GSEA). Our analyses revealed that class I and class II HDAC proteins are associated with distinct cancer phenotypes. The transcriptomic profiling indicated that class I HDAC members, including HDAC2, are positively associated with cancer stemness, while class IIA HDAC proteins, represented by HDAC7, show a negative correlation to cancer stem cell-like phenotypes in solid tumors. In contrast to tumors with high amounts of HDAC7 proteins, the transcriptome signatures of HDAC2-overexpressing cancers are significantly enriched with biological terms previously determined as stemness-associated genes. Moreover, high HDAC2-expressing tumors are depleted with immune-related processes, and HDAC2 expression correlates with tumor immunosuppressive microenvironments. On the contrary, HDAC7 upregulation is significantly associated with enhanced immune responses, followed by enriched infiltration of CD4+ and CD8+ T cells. This is the first comprehensive report demonstrating robust and versatile associations between specific HDAC family members, cancer dedifferentiation, and anti-tumor immune statuses in solid tumors.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The BET (bromodomain and extraterminal domain) family of proteins, particularly BRD4 (bromodomain-containing protein 4), plays a crucial role in transcription regulation and epigenetic mechanisms, impacting key cellular processes such as proliferation, differentiation, and the DNA damage response. BRD4, the most studied member of this family, binds to acetylated lysines on both histones and non-histone proteins, thereby regulating gene expression and influencing diverse cellular functions such as the cell cycle, tumorigenesis, and immune responses to viral infections. Given BRD4's involvement in these fundamental processes, it is implicated in various diseases, including cancer and inflammation, making it a promising target for therapeutic development. This review comprehensively explores the roles of the BET family in gene transcription, DNA damage response, and viral infection, discussing the potential of targeted small-molecule compounds and highlighting BET proteins as promising candidates for anticancer therapy.

Strong epigenetic pan-cancer biomarkers are required to meet several current, urgent clinical needs and to further improve the present chemotherapeutic standard. We have concentrated on the investigation of epigenetic alteration of the hTERT gene, which is frequently epigenetically dysregulated in a number of cancers in specific developmental stages. Distinct DNA methylation profiles were identified in our data on early urothelial cancer. An efficient EpihTERT assay could be developed utilizing suitable combinations with sequence-dependent thermodynamic parameters to distinguish between differentially methylated states. We infer from this data set, the epigenetic context, and the related literature that a CpG-rich, 2800 bp region, a prominent CpG island, surrounding the transcription start of the hTERT gene is the crucial epigenetic zone for the development of a potent biomarker. In order to accurately describe this region, we have named it "Acheron" (Ἀχέρων). In Greek mythology, this is the river of woe and misery and the path to the underworld. Exploitation of the DNA methylation profiles focused on this region, e.g., idiolocal normalized Methylation Specific PCR (IDLN-MSP), opens up a wide range of new possibilities for diagnosis, determination of prognosis, follow-up, and detection of residual disease. It may also have broad implications for the choice of chemotherapy.

Cancer risk is modulated by hereditary and somatic mutations, exposures, age, sex, and gender. The mechanisms by which sex and gender work alone and in combination with other cancer risk factors remain underexplored. In general, cancers that occur in both the male and female sexes occur more commonly in XY compared with XX individuals, regardless of genetic ancestry, geographic location, and age. Moreover, XY individuals are less frequently cured of their cancers, highlighting the need for a greater understanding of sex and gender effects in oncology. This will be necessary for optimal laboratory and clinical cancer investigations. To that end, we review the epigenetics of sexual differentiation and its effect on cancer hallmark pathways throughout life. Specifically, we will touch on how sex differences in metabolism, immunity, pluripotency, and tumor suppressor functions are patterned through the epigenetic effects of imprinting, sex chromosome complement, X inactivation, genes escaping X inactivation, sex hormones, and life history.

Histone deacetylase 1 (HDAC1), a class I HDAC enzyme, is crucial for histone modification. Currently, it is emerged as one of the important biological targets for designing small molecule drugs through cancer epigenetics. Along with synthetic inhibitors different natural inhibitors are showing potential HDAC1 inhibitions. In order to gain insights into the relationship between the molecular structures of the natural inhibitors and HDAC1, different molecular modelling techniques (Bayesian classification, recursive partitioning, molecular docking and molecular dynamics simulations) have been applied on a dataset of 155 HDAC1 nature-inspired inhibitors with diverse scaffolds. The Bayesian study showed acceptable ROC values for both the training set and test sets. The Recursive partitioning study produced decision tree 1 with 6 leaves. Further, molecular docking study was processed for generating the protein ligand complex which identified some potential amino acid residues such as F205, H28, L271, P29, F150, Y204 for the binding interactions in case of natural inhibitors. Stability of these HDAC1-natutal inhibitors complexes has been also evaluated by molecular dynamics simulation study. The current modelling study is an attempt to get a deep insight into the different important structural fingerprints among different natural compounds modulating HDAC1 inhibition.Communicated by Ramaswamy H. Sarma.