bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2021‒11‒21
seven papers selected by
Ankita Daiya
BITS Pilani

  1. Front Cell Dev Biol. 2021 ;9 739780
      Many of the cells in our bodies are quiescent, that is, temporarily not dividing. Under certain physiological conditions such as during tissue repair and maintenance, quiescent cells receive the appropriate stimulus and are induced to enter the cell cycle. The ability of cells to successfully transition into and out of a quiescent state is crucial for many biological processes including wound healing, stem cell maintenance, and immunological responses. Across species and tissues, transcriptional, epigenetic, and chromosomal changes associated with the transition between proliferation and quiescence have been analyzed, and some consistent changes associated with quiescence have been identified. Histone modifications have been shown to play a role in chromatin packing and accessibility, nucleosome mobility, gene expression, and chromosome arrangement. In this review, we critically evaluate the role of different histone marks in these processes during quiescence entry and exit. We consider different model systems for quiescence, each of the most frequently monitored candidate histone marks, and the role of their writers, erasers and readers. We highlight data that support these marks contributing to the changes observed with quiescence. We specifically ask whether there is a quiescence histone "code," a mechanism whereby the language encoded by specific combinations of histone marks is read and relayed downstream to modulate cell state and function. We conclude by highlighting emerging technologies that can be applied to gain greater insight into the role of a histone code for quiescence.
    Keywords:  histone acetylation; histone code; histone methylation; histone post translational modification; metabolism; quiescence
  2. Cancer Res. 2021 Nov 16. pii: canres.1940.2021. [Epub ahead of print]
      Heterogeneity is a pervasive feature of cancer, and understanding the sources and regulatory mechanisms underlying heterogeneity could provide key insights to help improve the diagnosis and treatment of cancer. In this review, we discuss the origin of heterogeneity in the phenotype of individual cancer cells. Genotype-phenotype (G-P) maps are widely used in evolutionary biology to represent the complex interactions of genes and the environment that lead to phenotypes that impact fitness. Here, we present the rationale of an extended G-P (eG-P) map with a cone structure in cancer. The eG-P cone is formed by cells that are similar at the genome layer but gradually increase variability in the epigenome, transcriptome, proteome, metabolome and signalome layers to produce large variability at the phenome layer. Experimental evidence from single-cell -omics analyses supporting the cancer eG-P cone concept is presented, and the impact of epimutations and the interaction of cancer and tumor microenvironmental eG-P cones are integrated with the current understanding of cancer biology. The eG-P cone concept uncovers potential therapeutic strategies to reduce cancer evolution and improve cancer treatment. More methods to study phenotypes in single cells will be key to better understand cancer cell fitness in tumor biology and therapeutics.
  3. Cell Stress. 2021 Nov;5(11): 167-172
      Dysregulated gene expression is intrinsic to cell transformation, tumorigenesis and metastasis. Cancer-specific gene-expression profiles stem from gene regulatory networks fueled by genetic and epigenetic defects, and by abnormal signals of the tumor microenvironment. These oncogenic signals ultimately engage the transcriptional machinery on the cis -regulatory elements of a host of effector genes, through recruitment of transcription factors (TFs), co-activators and chromatin regulators. That said, whether gene-expression in cancer cells is the chaotic product of myriad regulations or rather a relatively ordered process orchestrated by few TFs (master regulators) has long remained enigmatic. Recent work on the YAP/TAZ co-activators has been instrumental to break new ground into this outstanding issue, revealing that tumor cells hijack growth programs that are active during development and regeneration through engagement of a small set of interconnected TFs and their nuclear partners.
    Keywords:  AP-1; Brd4; Hippo; Mechanotransduction; YAP/TAZ; cancer; proliferation
  4. Autophagy. 2021 Nov 15. 1-3
      Mitochondria are critical organelles that maintain cellular metabolism and overall function. The catabolic pathway of autophagy plays a central role in recycling damaged mitochondria. Although the autophagy pathway is indispensable for some cancer cell survival, our latest study shows that rare autophagy-dependent cancer cells can adapt to loss of this core pathway. In the process, the autophagy-deficient cells acquire unique dependencies on alternate forms of mitochondrial homeostasis. These rare autophagy-deficient clones circumvent the lack of canonical autophagy by increasing mitochondrial dynamics and by recycling damaged mitochondria via mitochondrial-derived vesicles (MDVs). These studies are the first to implicate MDVs in cancer cell metabolism although many unanswered questions remain about this non-canonical pathway.
    Keywords:  Cancer; mitochondrial fusion; mitochondrial-derived vesicles; mitophagy; non-canonical autophagy
  5. Oncogenesis. 2021 Nov 13. 10(11): 76
      The histone methyltransferase G9a is well-documented for its implication in neoplastic growth. However, recent investigations have demonstrated a key involvement of this chromatin writer in maintaining the self-renewal and tumor-initiating capacities of cancer stem cells (CSCs). Direct inhibition of G9a's catalytic activity was reported as a promising therapeutic target in multiple preclinical studies. Yet, none of the available pharmacological inhibitors of G9a activity have shown success at the early stages of clinical testing. Here, we discuss central findings of oncogenic expression and activation of G9a in CSCs from different origins, as well as the impact of the suppression of G9a histone methyltransferase activity in such contexts. We will explore the challenges posed by direct and systemic inhibition of G9a activity in the perspective of clinical translation of documented small molecules. Finally, we will discuss recent advances in drug discovery as viable strategies to develop context-specific drugs, selectively targeting G9a in CSC populations.
  6. Mol Cell Biochem. 2021 Nov 18.
      Histones are classically known to organize the eukaryotic DNA into chromatin. They are one of the key players in regulating transcriptionally permissive and non-permissive states of the chromatin. Nevertheless, their context-dependent appearance within the cytoplasm and systemic circulation has also been observed. The past decade has also witnessed few scientific communications on the existence of vesicle-associated histones. Diverse groups have attempted to determine the significance of these extra-nuclear histones so far, with many of those studies still underway. Of note amongst these are interactions of extra-nuclear or free histones with cellular membranes, mediated by mutual cationic and anionic natures, respectively. It is here aimed to consolidate the mechanism of formation of extra-nuclear histones; implications of histone-induced membrane destabilization and explore the mechanisms of their association/release with extracellular vesicles, along with the functional aspects of these extra-nuclear histones in cell and systemic physiology.
    Keywords:  Cytoplasmic histones; Exosomal histones; Exosomes; Extra-nuclear histones; Vesicle-associated histones
  7. Cancer Manag Res. 2021 ;13 8411-8423
      Purpose: Long non-coding RNAs (lncRNAs) have diverse roles in modulating gene expression on both transcriptional and translational levels, but their involvement in osteosarcoma (OS) metastasis remains unknown.Patients and Methods: Transcriptional and clinical data were downloaded from TARGET datasets. A total of seven lncRNAs screened by univariate cox regression, lasso regression, and multivariate cox regression analysis were used to establish the OS metastasis model. The area under the receiver operating characteristic curve (AUC) was used to evaluate the model.
    Results: The established model showed exceptional predictive performance (1 year: AUC = 0.92, 95% Cl = 0.83-0.99; 3 years: AUC = 0.87, 95% Cl = 0.79-0.96; 5 years: AUC = 0.86, 95% Cl = 0.76-0.96). Patients in the high group had a poor survival outcome than those in the low group (p < 0.0001). GSEA analysis revealed that "NOTCH_SIGNALING" and "WNT_BETA_CATENIN_SIGNALING" were significantly enriched and that resting dendritic cells were associated with AL512422.1, AL357507.1, and AC006033.2 (p < 0.05).
    Conclusion: Based on seven prognosis-related lncRNAs, we constructed a novel model with high reliability and accuracy for predicting metastasis in OS patients.
    Keywords:  lncRNAs; osteosarcoma; prognosis; tumor metastasis