bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒02‒20
twelve papers selected by
Ankita Daiya, Birla Institute of Technology and Science



  1. Molecules. 2022 Jan 21. pii: 715. [Epub ahead of print]27(3):
      Histone deacetylases (HDACs) are a large family of epigenetic metalloenzymes that are involved in gene transcription and regulation, cell proliferation, differentiation, migration, and death, as well as angiogenesis. Particularly, disorders of the HDACs expression are linked to the development of many types of cancer and neurodegenerative diseases, making them interesting molecular targets for the design of new efficient drugs and imaging agents that facilitate an early diagnosis of these diseases. Thus, their selective inhibition or degradation are the basis for new therapies. This is supported by the fact that many HDAC inhibitors (HDACis) are currently under clinical research for cancer therapy, and the Food and Drug Administration (FDA) has already approved some of them. In this review, we will focus on the recent advances and latest discoveries of innovative strategies in the development and applications of compounds that demonstrate inhibitory or degradation activity against HDACs, such as PROteolysis-TArgeting Chimeras (PROTACs), tumor-targeted HDACis (e.g., folate conjugates and nanoparticles), and imaging probes (positron emission tomography (PET) and fluorescent ligands).
    Keywords:  PROTACs; dendrimers; fluorescent probes; folate conjugates; histone deacetylases (HDACs); nanoparticles; positron emission tomography (PET)
    DOI:  https://doi.org/10.3390/molecules27030715
  2. Cell Prolif. 2022 Feb 16. e13202
      Enhancers are important cis-acting elements that can regulate gene transcription and cell fate alongside promoters. In fact, many human cancers and diseases are associated with the malfunction of enhancers. Recent studies have shown that enhancers can produce enhancer RNAs (eRNAs) by RNA polymerase II. In this review, we discuss eRNA production, characteristics, functions and mechanics. eRNAs can determine chromatin accessibility, histone modification and gene expression by constructing a 'chromatin loop', thereby bringing enhancers to their target gene. eRNA can also be involved in the phase separation with enhancers and other proteins. eRNAs are abundant, and importantly, tissue-specific in tumours, various diseases and stem cells; thus, eRNAs can be a potential target for disease diagnosis and treatment. As eRNA is produced from the active transcription of enhancers and is involved in the regulation of cell fate, its manipulation will influence cell function, and therefore, it can be a new target for biological therapy.
    DOI:  https://doi.org/10.1111/cpr.13202
  3. Cancers (Basel). 2022 Jan 22. pii: 560. [Epub ahead of print]14(3):
      The alteration of epigenetic modifications often causes cancer onset and development. In a similar way, aberrant alternative splicing may result in oncogenic products. These issues have often been individually reviewed, but there is a growing body of evidence for the interconnection of both causes of cancer. Actually, aberrant splicing may result from abnormal epigenetic signalization and epigenetic factors may be altered by alternative splicing. In this way, the interrelation between epigenetic marks and alternative splicing form the base of a triangle, while cancer may be placed at the vertex. The present review centers on the interconnections at the triangle base, i.e., between alternative splicing and epigenetic modifications, which may result in neoplastic transformations. The effects of different epigenetic factors, including DNA and histone modifications, the binding of non-coding RNAs and the alterations of chromatin organization on alternative splicing resulting in cancer are first considered. Other less-frequently considered questions, such as the epigenetic regulation of the splicing machinery, the aberrant splicing of epigenetic writers, readers and erasers, etc., are next reviewed in their connection with cancer. The knowledge of the above-mentioned relationships has allowed increasing the collection of biomarkers potentially useful as cancer diagnostic and/or prognostic tools. Finally, taking into account on one hand that epigenetic changes are reversible, and some epigenetic drugs already exist and, on the other hand, that drugs intended for reversing aberrations in alternative splicing, therapeutic possibilities for breaking the mentioned cancer-related triangle are discussed.
    Keywords:  DNA methylation; alternative splicing; cancer; chromatin; epigenetics; histone acetylation; histone methylation
    DOI:  https://doi.org/10.3390/cancers14030560
  4. Biochem Pharmacol. 2022 Feb 07. pii: S0006-2952(22)00038-7. [Epub ahead of print]198 114944
      Fusion positive (FP) sarcomas are characterized by chromosomal rearrangements generating pathognomonic fusion transcripts and oncoproteins. In Ewing's sarcoma family of tumors (ESFTs), FP-rhabdomyosarcomas (FP-RMS) and synovial sarcomas (SS), the most common and aggressive forms of sarcomas in childhood and adolescence, the oncogenic rearrangements involve transcription cofactors causing widespread epigenetic rewiring and aberrant gene expression. Through the cooperation with histone deacetylases (HDACs) in transcription regulatory complexes, the fusion oncoproteins affect histone acetylation and chromatin remodeling. The participation of HDACs in core mechanisms of sarcoma cell transformation has paved the way to the investigation of HDAC inhibitors (HDACis) for therapeutic intervention. Preclinical studies have provided convincing evidence that HDAC activity abrogation can revert malignant cell features driven by FET-ETS, PAX3/7-FOXO1 or SS18-SSX fusion oncogenes in ESFTs, FP-RMS, or SS models, respectively, resulting in in vitro and in vivo growth inhibition. While clinical trials of HDACi monotherapies led to drug approval in some hematologic malignancies, no significant therapeutic benefit has been reported in solid tumors, including sarcomas. HDACi-based combination therapies with targeted or conventional anticancer agents have shown limited efficacy in early studies recruiting sarcoma patients, although partial responses and disease stabilization have been reported. In these trials, sarcomas were represented, however, as unclassified group in most cases. We summarize, here, studies addressing the role of HDACs in FP-sarcoma pathobiology and HDACi-based rational drug combinations. Finally, we discuss the opportunity of exploiting drug inhibitory profile and expression/function of specific HDAC isoenzymes to harness the full therapeutic potential of HDACis in these sarcoma histotypes.
    Keywords:  Drug combination; Ewing’s family of tumors; Fusion positive-rhabdomyosarcoma; Fusion-positive sarcomas; HAT; HDAC; HDAC inhibitor; Synovial sarcoma
    DOI:  https://doi.org/10.1016/j.bcp.2022.114944
  5. Cancers (Basel). 2022 Feb 01. pii: 763. [Epub ahead of print]14(3):
      Dysregulation of epigenetic mechanisms as well as genomic mutations contribute to the initiation and progression of cancer. In addition to histone code writers, including histone lysine methyltransferase (KMT), and histone code erasers, including histone lysine demethylase (KDM), histone code reader proteins such as HP1 are associated with abnormal chromatin regulation in human diseases. Heterochromatin protein 1 (HP1) recognizes histone H3 lysine 9 methylation and broadly affects chromatin biology, such as heterochromatin formation and maintenance, transcriptional regulation, DNA repair, chromatin remodeling, and chromosomal segregation. Molecular functions of HP1 proteins have been extensively studied, although their exact roles in diseases require further study. Here, we comprehensively review the studies that have revealed the altered expression of HP1 and its functions in tumorigenesis. In particular, the distinctive effects of each HP1 subtype, namely HP1α, HP1β, and HP1γ, have been thoroughly explored in various cancer types. We also highlight how HP1 can serve as a potential biomarker for cancer prognosis and therapeutic target for cancer patients.
    Keywords:  DDR; HP1; cancer; chromatin dynamics; epigenetic reader
    DOI:  https://doi.org/10.3390/cancers14030763
  6. Biochim Biophys Acta Rev Cancer. 2022 Feb 09. pii: S0304-419X(22)00022-1. [Epub ahead of print]1877(2): 188697
      Transcriptional deregulation of multiple oncogenes, tumor suppressors and survival pathways is a cancer cell hallmark. Super enhancers (SE) are long stretches of active enhancers in close linear proximity that ensure extraordinarily high expression levels of key genes associated with cell lineage, function and survival. SE landscape is intrinsically prone to changes and reorganization during the course of normal cell differentiation. This functional plasticity is typically utilized by cancer cells, which remodel their SE landscapes to ensure oncogenic transcriptional reprogramming. Multiple recent studies highlighted structural genetic mechanisms in non-coding regions that create new SE or hijack already existing ones. In addition, alterations in abundance/activity of certain SE-associated proteins or certain viral infections can elicit new super enhancers and trigger SE-driven transcriptional changes. For these reasons, SE profiling emerged as a powerful tool for discovering the core transcriptional regulatory circuits in tumor cells. This, in turn, provides new insights into cancer cell biology, and identifies main nodes of key cellular pathways to be potentially targeted. Since SEs are susceptible to inhibition, their disruption results in exponentially amassing 'butterfly' effect on gene expression and cell function. Moreover, many of SE elements are druggable, opening new therapeutic opportunities. Indeed, SE targeting drugs have been studied preclinically in various hematologic malignancies with promising effects. Herein, we review the unique features of SEs, present different cis- and trans-acting mechanisms through which hematologic tumor cells acquire SEs, and finally, discuss the potential of SE targeting in the therapy of hematologic malignancies.
    Keywords:  Enhancer RNA; Phase separation; Super-enhancer; Transcriptional addiction; Transcriptional deregulation
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188697
  7. Life Sci Alliance. 2022 05;pii: e202101114. [Epub ahead of print]5(5):
      Neointimal hyperplasia/proliferation (IH) is the primary etiology of vascular stenosis. Epigenomic studies concerning IH have been largely confined to in vitro models, and IH-underlying epigenetic mechanisms remain poorly understood. This study integrates information from in vivo epigenomic mapping, conditional knockout, gene transfer and pharmacology in rodent models of IH. The data from injured (IH-prone) rat arteries revealed a surge of genome-wide occupancy by histone-3 lysine-27 trimethylation (H3K27me3), a gene-repression mark. This was unexpected in the traditional view of prevailing post-injury gene activation rather than repression. Further analysis illustrated a shift of H3K27me3 enrichment to anti-proliferative genes, from pro-proliferative genes where gene-activation mark H3K27ac(acetylation) accumulated instead. H3K27ac and its reader BRD4 (bromodomain protein) co-enriched at Ezh2; conditional BRD4 knockout in injured mouse arteries reduced H3K27me3 and its writer EZH2, which positively regulated another pro-IH chromatin modulator UHRF1. Thus, results uncover injury-induced loci-specific H3K27me3 redistribution in the epigenomic landscape entailing BRD4→EZH2→UHRF1 hierarchical regulations. Given that these players are pharmaceutical targets, further research may help improve treatments of IH.
    DOI:  https://doi.org/10.26508/lsa.202101114
  8. Curr Opin Cell Biol. 2022 Feb 12. pii: S0955-0674(22)00004-7. [Epub ahead of print]74 62-70
      Temporal and spatial specificity of gene expression is highly regulated through a rich milieu of regulatory DNAs embedded in the genome. Enhancers represent a major class of regulatory DNAs that consist of a cluster of binding sites for sequence-specific transcription factors and are thought to facilitate recruitment of transcription machinery to their target promoters from remote locations. It has been over four decades since the discovery of prototypic simian virus 40 enhancer, yet the nature of enhancer-promoter interaction still remains an outstanding mystery in gene regulation. The aim of this review is to comprehensively overview molecular mechanisms underlying enhancer-promoter interaction including the roles of looping factors, higher-order genome topology, and dynamic clustering of transcription apparatus within a nucleus. We propose that cooperative interplay between 'looping' and 'hub' permits distal enhancers to specifically and dynamically modulate target gene expression over large distances.
    Keywords:  Enhancer; Genome topology; Looping; Promoter; Transcription; Transcription hub
    DOI:  https://doi.org/10.1016/j.ceb.2022.01.003
  9. Cancers (Basel). 2022 Jan 27. pii: 655. [Epub ahead of print]14(3):
      To be dormant or not depends on the origin and nature of both the cell and its niche. Similar to other cancer hallmarks, dormancy is ingrained with stemness, and stemness is embedded within dormancy. After all, cancer dormancy is dependent on multiple factors such as cell cycle arrest, metabolic inactivity, and the microenvironment. It is the net results and sum effects of a myriad of cellular interactions, interconnections, and interplays. When we unite all cancer networks and integrate all cancer hallmarks, we practice and preach a unified theory of cancer. From this perspective, we review cancer dormancy in the context of a stem cell theory of cancer. We revisit the seed and soil hypothesis of cancer. We reexamine its implications in both primary tumors and metastatic lesions. We reassess its roles in cell cycle arrest, metabolic inactivity, and stemness property. Cancer dormancy is particularly revealing when it informs us about the mysteries of late relapse, prolonged remission, and second malignancy. It is paradoxically rewarding when it delivers us the promises and power of cancer prevention and maintenance therapy in patient care.
    Keywords:  cancer dormancy; cancer stem cells; clonal origin; late relapse; prolonged remission; second malignancy; seed and soil; stress; unified theory
    DOI:  https://doi.org/10.3390/cancers14030655
  10. Nat Cell Biol. 2022 Feb 17.
      Metabolic reprogramming is central to oncogene-induced tumorigenesis by providing the necessary building blocks and energy sources, but how oncogenic signalling controls metabolites that play regulatory roles in driving cell proliferation and tumour growth is less understood. Here we show that oncogene YAP/TAZ promotes polyamine biosynthesis by activating the transcription of the rate-limiting enzyme ornithine decarboxylase 1. The increased polyamine levels, in turn, promote the hypusination of eukaryotic translation factor 5A (eIF5A) to support efficient translation of histone demethylase LSD1, a transcriptional repressor that mediates a bulk of YAP/TAZ-downregulated genes including tumour suppressors in YAP/TAZ-activated cells. Accentuating the importance of the YAP/TAZ-polyamine-eIF5A hypusination-LSD1 axis, inhibiting polyamine biosynthesis or LSD1 suppressed YAP/TAZ-induced cell proliferation and tumour growth. Given the frequent upregulation of YAP/TAZ activity and polyamine levels in diverse cancers, our identification of YAP/TAZ as an upstream regulator and LSD1 as a downstream effector of the oncometabolite polyamine offers a molecular framework in which oncogene-induced metabolic and epigenetic reprogramming coordinately drives tumorigenesis, and suggests potential therapeutic strategies in YAP/TAZ- or polyamine-dependent human malignancies.
    DOI:  https://doi.org/10.1038/s41556-022-00848-5
  11. Int J Mol Sci. 2022 Feb 01. pii: 1691. [Epub ahead of print]23(3):
      Histone post-translational modifications are small chemical changes to the histone protein structure that have cascading effects on diverse cellular functions. Detecting histone modifications and characterizing their binding partners are critical steps in understanding chromatin biochemistry and have been accessed using common reagents such as antibodies, recombinant assays, and FRET-based systems. High-throughput platforms could accelerate work in this field, and also could be used to engineer de novo histone affinity reagents; yet, published studies on their use with histones have been noticeably sparse. Here, we describe specific experimental conditions that affect binding specificities of post-translationally modified histones in classic protein engineering platforms and likely explain the relative difficulty with histone targets in these platforms. We also show that manipulating avidity of binding interactions may improve specificity of binding.
    Keywords:  affinity reagents; antibody; binder; chromodomain; epigenome engineering; histone post-translational modifications; protein engineering; reader; synthetic biology; yeast surface display
    DOI:  https://doi.org/10.3390/ijms23031691
  12. Int J Mol Sci. 2022 Feb 03. pii: 1733. [Epub ahead of print]23(3):
      Hedgehog (Hh) signaling is a highly conserved pathway that plays a vital role during embryonic development. Recently, uncontrolled activation of this pathway has been demonstrated in various types of cancer. Therefore, Hh pathway inhibitors have emerged as an important class of anti-cancer agents. Unfortunately, however, their reputation has been tarnished by the emergence of resistance during therapy, necessitating clarification of mechanisms underlying the drug resistance. In this review, we briefly overview canonical and non-canonical Hh pathways and their inhibitors as targeted cancer therapy. In addition, we summarize the mechanisms of resistance to Smoothened (SMO) inhibitors, including point mutations of the drug binding pocket or downstream molecules of SMO, and non-canonical mechanisms to reinforce Hh pathway output. A distinct mechanism involving loss of primary cilia is also described to maintain GLI activity in resistant tumors. Finally, we address the main strategies to circumvent the drug resistance. These strategies include the development of novel and potent inhibitors targeting different components of the canonical Hh pathway or signaling molecules of the non-canonical pathway. Further studies are necessary to avoid emerging resistance to Hh inhibitors and establish an optimal customized regimen with improved therapeutic efficacy to treat various types of cancer, including basal cell carcinoma.
    Keywords:  basal cell carcinoma; drug resistance; hedgehog inhibitor; hedgehog signaling; smoothened inhibitor; targeted cancer therapy
    DOI:  https://doi.org/10.3390/ijms23031733