bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2021–12–19
seven papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Histone Deacetylase Inhibitors, Intrinsic and Extrinsic Apoptotic Pathways, and Epigenetic Alterations of Histone Deacetylases (HDACs) in Hepatocellular Carcinoma.
  2. Deciphering functional tumor states at single-cell resolution.
  3. Single-Cell RNA Sequencing Analysis of the Heterogeneity in Gene Regulatory Networks in Colorectal Cancer.
  4. p53 mutations define the chromatin landscape to confer drug tolerance in pancreatic cancer.
  5. Dynamic transcription regulation at the single-molecule level.
  6. Rushika M. Perera: Lysosomes unveil what cancer cells hide.
  7. Heat shock proteins in cell signaling and cancer.
  1. Iran J Pharm Res. 2021 ;20(3): 324-336
    Histone Deacetylase Inhibitors, Intrinsic and Extrinsic Apoptotic Pathways, and Epigenetic Alterations of Histone Deacetylases (HDACs) in Hepatocellular Carcinoma.
    Masumeh Sanaei, Fraidoon Kavoosi.
      Epigenetics is the study of heritable modifications in gene expression and reversible forms of gene regulation. Recent in-vitro works have indicated that epigenetics plays a significant role in many types of human cancers e.g. hepatocellular carcinoma (HCC). Diverse cellular functions are regulated by histone acetylation and deacetylation. Histone deacetylases (HDACs) and histone acetylases (HATs) are enzymes involved in chromatin remodeling histone deacetylation and acetylation respectively. Aberrant protein acetylation, particularly histone deacetylation, has been reported in a broad range of human cancer types. Epigenetic modification by inhibiting HDAC activity is an emerging approach in cancer treatment. HDACIs play their apoptotic roles through multiple mechanisms such as extrinsic/cytoplasmic and intrinsic/mitochondrial molecular mechanisms. Here, we summarize the major classes of HDACs and epigenetic compounds, HDACIs, and also their molecular mechanisms in HCC including intrinsic and extrinsic apoptotic pathways. An online search of different sources including PubMed, ISI, and Scopus was achieved to find suitable data on mechanisms and pathways of HDACs and HDACIs in HCC. The result demonstrated that the dysregulation of HDACs because of histone deacetylation induces HCC. The histone deacetylation can be reversed by HDACIs resulting in apoptosis induction. In conclusion, because histone deacetylation is a potentially reversible change, epigenetic histone modification represents new opportunities for cancer management by reactivation of gene silencing. The inhibition of HDACs by GDACIs can effectively induce apoptosis and suppress cancer cell proliferation. These compounds can engage both intrinsic and extrinsic apoptotic pathways.
    Keywords:  Apoptosis; HDACIs; HDACS; Neoplasms; Pathway
    DOI:  https://doi.org/10.22037/ijpr.2021.115105.15197
  2. EMBO J. 2021 Dec 17. e109221
    Deciphering functional tumor states at single-cell resolution.
    Rolando Vegliante, Ievgenia Pastushenko, Cédric Blanpain.
      Within a tumor, cancer cells exist in different states that are associated with distinct tumor functions, including proliferation, differentiation, invasion, metastasis, and resistance to anti-cancer therapy. The identification of the gene regulatory networks underpinning each state is essential for better understanding functional tumor heterogeneity and revealing tumor vulnerabilities. Here, we review the different studies identifying tumor states by single-cell sequencing approaches and the mechanisms that promote and sustain these functional states and regulate their transitions. We also describe how different tumor states are spatially distributed and interact with the specific stromal cells that compose the tumor microenvironment. Finally, we discuss how the understanding of tumor plasticity and transition states can be used to develop new strategies to improve cancer therapy.
    Keywords:  EMT; cancer therapy; metastasis; single-cell; tumor heterogeneity
    DOI:  https://doi.org/10.15252/embj.2021109221
  3. Front Cell Dev Biol. 2021 ;9 765578
    Single-Cell RNA Sequencing Analysis of the Heterogeneity in Gene Regulatory Networks in Colorectal Cancer.
    Rui-Qi Wang, Wei Zhao, Hai-Kui Yang, Jia-Mei Dong, Wei-Jie Lin, Fa-Zhong He, Min Cui, Zhi-Ling Zhou.
      Colorectal cancer (CRC) manifests as gastrointestinal tumors with high intratumoral heterogeneity. Recent studies have demonstrated that CRC may consist of tumor cells with different consensus molecular subtypes (CMS). The advancements in single-cell RNA sequencing have facilitated the development of gene regulatory networks to decode key regulators for specific cell types. Herein, we comprehensively analyzed the CMS of CRC patients by using single-cell RNA-sequencing data. CMS for all malignant cells were assigned using CMScaller. Gene set variation analysis showed pathway activity differences consistent with those reported in previous studies. Cell-cell communication analysis confirmed that CMS1 was more closely related to immune cells, and that monocytes and macrophages play dominant roles in the CRC tumor microenvironment. On the basis of the constructed gene regulation networks (GRNs) for each subtype, we identified that the critical transcription factor ERG is universally activated and upregulated in all CMS in comparison with normal cells, and that it performed diverse roles by regulating the expression of different downstream genes. In summary, molecular subtyping of single-cell RNA-sequencing data for colorectal cancer could elucidate the heterogeneity in gene regulatory networks and identify critical regulators of CRC.
    Keywords:  ERG; colorectal cancer; consensus molecular subtypes; gene regulation networks; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fcell.2021.765578
  4. Mol Oncol. 2021 Dec 17.
    p53 mutations define the chromatin landscape to confer drug tolerance in pancreatic cancer.
    Carlotta Zampieri, Emanuele Panatta, Vincenzo Corbo, Alessandro Mauriello, Gerry Melino, Ivano Amelio.
      Somatic inactivation of p53 (TP53) mainly occurs as missense mutations that lead to acquisition of neomorphic mutant protein forms. p53 mutants have been postulated to exert gain-of-function (GOF) effects, including promotion of metastasis and drug tolerance, which generally contribute to acquisition of the lethal phenotype. Here, by integrating a p53R270H -dependent transcriptomic analysis with chromatin accessibility (ATAC-seq) profiling, we shed light on the molecular basis of a p53 mutant-dependent drug-tolerant phenotype in pancreatic cancer. p53R270H finely tunes chromatin accessibility in specific genomic loci, orchestrating a transcriptional programme that participates to phenotypic evolution of the cancer. We specifically focused on the p53R270H -dependent regulation of the tyrosine kinase receptor macrophage-stimulating protein receptor (MST1r). MST1r deregulation substantially impinged on drug response in the experimental model, recapitulating the p53R270H -dependent phenotype, and strongly correlated with p53 mutant and aggressive phenotype in pancreatic cancer patients. As cellular plasticity in the final stages of evolution of pancreatic cancer seems to predominantly originate from epigenetic mechanisms, we propose that mutant p53 participates in acquisition of a lethal phenotype by fine-tuning the chromatin landscape.
    Keywords:  Chromatin modifications; SWI/SNF chromatin remodeling complex; cancer epigenetics; chemoresistance; chemosensitivity; gemcitabine treatment
    DOI:  https://doi.org/10.1002/1878-0261.13161
  5. Dev Biol. 2021 Dec 09. pii: S0012-1606(21)00236-0. [Epub ahead of print]
    Dynamic transcription regulation at the single-molecule level.
    Zuhui Wang, Wulan Deng.
      Cell fate changes during development, differentiation, and reprogramming are largely controlled at the transcription level. The DNA-binding transcription factors (TFs) often act in a combinatorial fashion to alter chromatin states and drive cell type-specific gene expression. Recent advances in fluorescent microscopy technologies have enabled direct visualization of biomolecules involved in the process of transcription and its regulatory events at the single-molecule level in living cells. Remarkably, imaging and tracking individual TF molecules at high temporal and spatial resolution revealed that they are highly dynamic in searching and binding cognate targets, rather than static and binding constantly. In combination with investigation using techniques from biochemistry, structure biology, genetics, and genomics, a more well-rounded view of transcription regulation is emerging. In this review, we briefly cover the technical aspects of live-cell single-molecule imaging and focus on the biological relevance and interpretation of the single-molecule dynamic features of transcription regulatory events observed in the native chromatin environment of living eukaryotic cells. We also discuss how these dynamic features might shed light on mechanistic understanding of transcription regulation.
    Keywords:  Chromatin regulation; RNA polymerase II; Single-molecule imaging; Transcription factor
    DOI:  https://doi.org/10.1016/j.ydbio.2021.11.004
  6. J Cell Biol. 2022 Jan 03. pii: e202112049. [Epub ahead of print]221(1):
    Rushika M. Perera: Lysosomes unveil what cancer cells hide.
    Lucia Morgado-Palacin.
      Rushika M. Perera studies how pancreatic cancer cells use autophagy and the lysosome to adapt to stress.
    DOI:  https://doi.org/10.1083/jcb.202112049
  7. Biochim Biophys Acta Mol Cell Res. 2021 Dec 11. pii: S0167-4889(21)00241-X. [Epub ahead of print] 119187
    Heat shock proteins in cell signaling and cancer.
    Benjamin J Lang, Thomas L Prince, Yuka Okusha, Heeyoun Bunch, Stuart K Calderwood.
      Heat Shock Proteins (HSPs) and their co-chaperones have well-established roles in regulating proteostasis within the cell, the nature of which continues to emerge with further study. To date, HSPs have been shown to be integral to protein folding and re-folding, protein transport, avoidance of protein aggregation, and modulation of protein degradation. Many cell signaling events are mediated by the chemical modification of proteins post-translationally that can alter protein conformation and activity, although it is not yet known whether the changes in protein conformation induced by post-translational modifications (PTMs) are also dependent upon HSPs and their co-chaperones for subsequent protein re-folding. We discuss what is known regarding roles for HSPs and other molecular chaperones in cell signaling events with a focus on oncogenic signaling. We also propose a hypothesis by which Hsp70 and Hsp90 may co-operate to facilitate cell signaling events that may link PTMs with the cellular protein folding machinery.
    Keywords:  Cancer; Cell signaling; Co-chaperones; Heat; Hsp70; Kinases; Oncogenic signal transduction; Phosphorylation; Post-translational modifications (PTM); Proteins; Shock
    DOI:  https://doi.org/10.1016/j.bbamcr.2021.119187
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