bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒01‒02
twelve papers selected by
Ankita Daiya
BITS Pilani

  1. FEBS J. 2021 Dec 25.
      Metastasis, therapy failure and tumor recurrence are major clinical challenges in cancer. The interplay between tumor initiating cells (TICs) and Epithelial-Mesenchymal transition (EMT) drives tumor progression and spread. Recent advances have highlighted the involvement of epigenetic deregulation in these processes. The Euchromatin Histone Lysine Methyltransferase 1 (EHMT1) and Euchromatin Histone Lysine Methyltransferase 2 (EHMT2) that primarily mediate histone 3 lysine 9 di-methylation (H3K9me2), as well as methylation of non-histone proteins, are now recognized to be aberrantly expressed in many cancers. Their deregulated expression is associated with EMT, cellular plasticity and therapy resistance. In this review, we summarize evidence of their myriad roles in cancer metastasis, stemness and drug resistance. We discuss cancer-type specific molecular targets, context-dependent mechanisms and future directions of research in targeting EHMT1/EHMT2 for the treatment of cancer.
    Keywords:  Cancer Stem Cells; Drug resistance; EMT; G9a; GLP; Metabolism; Metastasis; Methylation; Therapeutics
  2. J Biochem. 2021 Dec 30. pii: mvab139. [Epub ahead of print]
      In eukaryotic cells, DNA is tightly compacted as chromatin. Chromatin states must be dynamically changed to increase the accessibility of transcription factors to chromatin or to stably silence genes by higher-order chromatin structures known as heterochromatin. The regulation of chromatin needs cooperative action performed by a variety of proteins. Specific binding of transcription factors to target DNA is the initial step of chromatin regulation, and promotes changes in the post-translational modifications of histone tails, which themselves are recognized by a set of histone reader proteins. Recent biochemical studies have revealed that some transcription factors that recognize specific DNA sequences can also interact with histones. Furthermore, histone reader proteins that recognize specific histone tail modifications have been shown to have the ability to directly bind to DNA. In this commentary, we introduce recent advances in the elucidation of how chromatin regulating factors recognize nucleosomal targets.
    Keywords:  heterochromatin; histone methylation; histone reader; nucleosome; pioneer transcription factor
  3. Epigenomes. 2021 Oct 08. pii: 22. [Epub ahead of print]5(4):
      Aberrant DNA methylation, dysregulation of chromatin-modifying enzymes, and microRNAs (miRNAs) play a crucial role in haematological malignancies. These epimutations, with an impact on chromatin accessibility and transcriptional output, are often associated with genomic instability and the emergence of drug resistance, disease progression, and poor survival. In order to exert their functions, epigenetic enzymes utilize cellular metabolites as co-factors and are highly dependent on their availability. By affecting the expression of metabolic enzymes, epigenetic modifiers may aid the generation of metabolite signatures that could be utilized as targets and biomarkers in cancer. This interdependency remains often neglected and poorly represented in studies, despite well-established methods to study the cellular metabolome. This review critically summarizes the current knowledge in the field to provide an integral picture of the interplay between epigenomic alterations and the cellular metabolome in haematological malignancies. Our recent findings defining a distinct metabolic signature upon response to enhancer of zeste homolog 2 (EZH2) inhibition in multiple myeloma (MM) highlight how a shift of preferred metabolic pathways may potentiate novel treatments. The suggested link between the epigenome and the metabolome in haematopoietic tumours holds promise for the use of metabolic signatures as possible biomarkers of response to treatment.
    Keywords:  epigenetic; gene regulation; haematological malignancies; metabolite
  4. Curr Med Chem. 2021 Dec 28.
      DNA is packaged in rolls in an octamer of histones forming a complex of DNA and proteins called chromatin. Chromatin as a structural matrix of a chromosome and its modifications are nowadays considered relevant aspects for regulating gene expression, which has become of high interest in understanding genetic mechanisms regulating various diseases, including cancer. In various types of cancer, the main modifications are found to be DNA methylation in the CpG dinucleotide as a silencing mechanism in transcription, post-translational histone modifications such as acetylation, methylation and others that affect the chromatin structure, the ATP-dependent chromatin remodeling and miRNA-mediated gene silencing. In this review we analyze the main alterations in gene expression, the epigenetic modification patterns that cancer cells present, as well as the main modulators and inhibitors of each epigenetic mechanism and the molecular evolution of the most representative inhibitors, which have opened a promising future in the study of HAT, HDAC, non-glycoside DNMT inhibitors and domain inhibitors.
    Keywords:  Cancer; DNA; chromatin; epigenetic inhibitor; epigenoma.; histone
  5. Epigenomes. 2020 Aug 17. pii: 17. [Epub ahead of print]4(3):
      Chromatin regulators of the Polycomb group of genes are well-known by their activities as transcriptional repressors. Characteristically, their presence at genomic sites occurs with specific histone modifications and sometimes high-order chromatin structures correlated with silencing of genes involved in cell differentiation. However, evidence gathered in recent years, on flies and mammals, shows that in addition to these sites, Polycomb products bind to a large number of active regulatory regions. Occupied sites include promoters and also intergenic regions, containing enhancers and super-enhancers. Contrasting with occupancies at repressed targets, characteristic histone modifications are low or undetectable. Functions on active targets are dual, restraining gene expression at some targets while promoting activity at others. Our aim here is to summarize the evidence available and discuss the convenience of broadening the scope of research to include Polycomb functions on active targets.
    Keywords:  Polycomb; RING1B; active targets; differentiation; enhancer; fine-tuning regulation; promoter
  6. Proc Natl Acad Sci U S A. 2022 Jan 04. pii: e2116222119. [Epub ahead of print]119(1):
      Nuclear noncoding RNAs (ncRNAs) are key regulators of gene expression and chromatin organization. The progress in studying nuclear ncRNAs depends on the ability to identify the genome-wide spectrum of contacts of ncRNAs with chromatin. To address this question, a panel of RNA-DNA proximity ligation techniques has been developed. However, neither of these techniques examines proteins involved in RNA-chromatin interactions. Here, we introduce RedChIP, a technique combining RNA-DNA proximity ligation and chromatin immunoprecipitation for identifying RNA-chromatin interactions mediated by a particular protein. Using antibodies against architectural protein CTCF and the EZH2 subunit of the Polycomb repressive complex 2, we identify a spectrum of cis- and trans-acting ncRNAs enriched at Polycomb- and CTCF-binding sites in human cells, which may be involved in Polycomb-mediated gene repression and CTCF-dependent chromatin looping. By providing a protein-centric view of RNA-DNA interactions, RedChIP represents an important tool for studies of nuclear ncRNAs.
    Keywords:  CTCF; Polycomb; RNA–DNA interactome; cell nucleus; noncoding RNA
  7. ACS Synth Biol. 2021 Dec 29.
      Chromatin structure contains critical epigenetic information in various forms, such as histone post-translational modifications (PTMs). The deposition of certain histone PTMs can remodel the chromatin structure, resulting in gene expression alteration. The epigenetic information carried by histone PTMs could be inherited by daughter cells to maintain the gene expression status. Recently, studies revealed that several conserved replisome proteins regulate the recycling of parental histones carrying epigenetic information in Saccharomyces cerevisiae. Hence, the proper recycling and deposition of parental histones onto newly synthesized DNA strands is presumed to be essential for epigenetic inheritance. Here, we first reviewed the fundamental mechanisms of epigenetic modification establishment and maintenance discovered within fungal models. Next, we discussed the functions of parental histone chaperones and the potential impacts of the parental histone recycling process on heterochromatin-mediated transcriptional silencing inheritance. Subsequently, we summarized novel synthetic biology approaches developed to analyze individual epigenetic components during epigenetic inheritance in fungal and mammalian systems. These newly emerged research paradigms enable us to dissect epigenetic systems in a bottom-up manner. Furthermore, we highlighted the approaches developed in this emerging field and discussed the potential applications of these engineered regulators to building synthetic epigenetic systems.
    Keywords:  epigenetic inheritance; epigenome editing; fungi; heterochromatin; synthetic epigenetics
  8. Methods Mol Biol. 2022 ;2445 139-169
      Anticancer therapy is complicated by the ability of malignant cells to activate cytoprotective autophagy that rescues treated cells. This protocol describes methods for analysis of autophagic process in apoptosis-resistant tumor cells treated with damaging agents. Induction of autophagy in these cells can activate apoptotic death. Protocol provides methods for Western blotting, immunofluorescent analysis, and transfection of cells with fluorescent protein-tagged LC3-encoding plasmids to analyze autophagy. Different approaches to change autophagy in tumor cells are suggested. A special approach is connected with induction of cellular senescence. Senescent cells, which are resistant to apoptosis, are vulnerable to certain damaging agents, in particular, to kinase inhibitors. Methods to induce and analyze senescence are considered. They include detection of proliferation arrest by different ways, mTORC1 activity assay and fluorescent analysis of mTORC1 and lysosome localization as a novel senescence hallmark. Incapability of senescent cells to complete autophagy after damage allows to force them to apoptosis. To demonstrate apoptotic cell death, analysis of caspase activity, Annexin V-FITC binding, DNA fragmentation, and mitochondria and lysosome damage are suggested. The methods described can be applied in studies aimed on developing different strategies of tumor cell elimination through changing autophagy.
    Keywords:  Apoptotic cell death; Autophagic cell death; Autophagy; Cancer; Cytoplasmic compartmentalization; Senescence; mTORC1
  9. Front Cell Dev Biol. 2021 ;9 740009
      The human body is normally adapted to maintain homeostasis in a terrestrial environment. The novel conditions of a space environment introduce challenges that changes the cellular response to its surroundings. Such an alteration causes physical changes in the extracellular microenvironment, inducing the secretion of cytokines such as interleukin-6 (IL-6) and tumor growth factor-β (TGF-β) from cancer cells to enhance cancer malignancy. Cancer is one of the most prominent cell types to be affected by mechanical cues via active interaction with the tumor microenvironment. However, the mechanism by which cancer cells mechanotransduce in the space environment, as well as the influence of this process on human health, have not been fully elucidated. Due to the growing interest in space biology, this article reviews cancer cell responses to the representative conditions altered in space: microgravity, decompression, and irradiation. Interestingly, cytokine and gene expression that assist in tumor survival, invasive phenotypic transformation, and cancer cell proliferation are upregulated when exposed to both simulated and actual space conditions. The necessity of further research on space mechanobiology such as simulating more complex in vivo experiments or finding other mechanical cues that may be encountered during spaceflight are emphasized.
    Keywords:  cancer Progression; cellular mechanoadaptation; mechanotransduction; microgravity; space mechanobiology
  10. Mol Cell. 2021 Dec 20. pii: S1097-2765(21)01038-8. [Epub ahead of print]
      Ferroptosis is a unique type of non-apoptotic cell death resulting from the unrestrained occurrence of peroxidized phospholipids, which are subject to iron-mediated production of lethal oxygen radicals. This cell death modality has been detected across many organisms, including in mammals, where it can be used as a defense mechanism against pathogens or even harnessed by T cells to sensitize tumor cells toward effective killing. Conversely, ferroptosis is considered one of the main cell death mechanisms promoting degenerative diseases. Emerging evidence suggests that ferroptosis represents a vulnerability in certain cancers. Here, we critically review recent advances linking ferroptosis vulnerabilities of dedifferentiating and persister cancer cells to the dependency of these cells on iron, a potential Achilles heel for small-molecule intervention. We provide a perspective on the mechanisms reliant on iron that contribute to the persister cancer cell state and how this dependency may be exploited for therapeutic benefits.
  11. Genome Res. 2021 Dec 28.
      Chromosome organization and dynamics are involved in regulating many fundamental processes such as gene transcription and DNA repair. Experiments unveiled that chromatin motion is highly heterogeneous inside cell nuclei, ranging from a liquid-like, mobile state to a gel-like, rigid regime. Using polymer modeling, we investigate how these different physical states and dynamical heterogeneities may emerge from the same structural mechanisms. We found that the formation of topologically associating domains (TADs) is a key driver of chromatin motion heterogeneity. In particular, we showed that the local degree of compaction of the TAD regulates the transition from a weakly compact, fluid state of chromatin to a more compact, gel state exhibiting anomalous diffusion and coherent motion. Our work provides a comprehensive study of chromosome dynamics and a unified view of chromatin motion enabling interpretation of the wide variety of dynamical behaviors observed experimentally across different biological conditions, suggesting that the "liquid" or "solid" state of chromatin are in fact two sides of the same coin.
  12. Eur J Med Chem. 2021 Dec 18. pii: S0223-5234(21)00898-9. [Epub ahead of print]229 114049
      Histone deacetylases (HDAC) are clinically validated and attractive epigenetic drug targets for human cancers. Several HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to the poor pharmacokinetics, bioavailability, selectivity of the HDAC inhibitors and most of them need to be combined with other drugs to achieve better results. Here, we describe our efforts toward the discovery of a novel series of lactam-based derivatives as selective HDAC inhibitors. Intensive structural modifications lead to the identification of compound 24g as the most active Class I HDAC Inhibitor, along with satisfactory metabolic stability in vitro (t1/2, human = 797 min) and the desirable oral bioavailability (F = 92%). More importantly, compound 24g showed good antitumor efficacy in a TMD-8 xenograft model (TGI = 77%) without obvious toxicity. These results indicated that Class I HDAC Inhibitor could be potentially used to treat certain diffuse large B-cell lymphoma therapeutics.
    Keywords:  Bioavailability; Diffuse large B-Cell lymphoma; HDAC; Inhibitors; Metabolic stability