bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023‒11‒19
eight papers selected by
Ankita Daiya, BITS Pilani

  1. Semin Cell Dev Biol. 2023 Nov 15. pii: S1084-9521(23)00229-X. [Epub ahead of print]156 1-10
      The emergence of therapeutic resistance remains a formidable barrier to durable responses by cancer patients and is a major cause of cancer-related deaths. It is increasingly recognized that non-genetic mechanisms of acquired resistance are important in many cancers. These mechanisms of resistance rely on inherent cellular plasticity where cancer cells can switch between multiple phenotypic states without genetic alterations, providing a dynamic, reversible resistance landscape. Such mechanisms underlie the generation of drug-tolerant persister (DTP) cells, a subpopulation of tumour cells that contributes to heterogeneity within tumours and that supports therapeutic resistance. In this review, we provide an overview of the major features of DTP cells, focusing on phenotypic and metabolic plasticity as two key drivers of tolerance and persistence. We discuss the link between DTP cell plasticity and the potential vulnerability of these cells to ferroptosis. We also discuss the relationship between DTP cells and cells that survive the induction of apoptosis, a process termed anastasis, and discuss the properties of such cells in the context of increased metastatic potential and sensitivity to cell death mechanisms such as ferroptosis.
    Keywords:  Anastasis; Drug tolerant persister cell; Epithelial-to-mesenchymal transition; Ferroptosis; Plasticity; Therapy resistance
  2. Acta Biomater. 2023 Nov 15. pii: S1742-7061(23)00661-X. [Epub ahead of print]
      Cells cultured on stiff 2D substrates exert high intracellular force, resulting in mechanical deformation of their nuclei. This nuclear deformation (ND) plays a crucial role in the transport of Yes Associated Protein (YAP) from the cytoplasm to the nucleus. However, cells in vivo are in soft 3D environment with potentially much lower intracellular forces. Whether and how cells may deform their nuclei in 3D for YAP localization remains unclear. Here, by culturing human colon cancer associated fibroblasts (CAFs) on 2D, 2.5D, and 3D substrates, we differentiated the effects of stiffness, force, and ND on YAP localization. We found that nuclear translocation of YAP depends on the degree of ND irrespective of dimensionality, stiffness and total force. ND induced by the perinuclear force, not the total force, and nuclear membrane curvature correlate strongly with YAP activation. Immunostained slices of human tumors further supported the association between ND and YAP nuclear localization, suggesting ND as a potential biomarker for YAP activation in tumors. Additionally, we conducted quantitative analysis of the force dynamics of CAFs on 2D substrates to construct a stochastic model of YAP kinetics. This model revealed that the probability of YAP nuclear translocation, as well as the residence time in the nucleus follow a power law. This study provides valuable insights into the regulatory mechanisms governing YAP dynamics and highlights the significance of threshold activation in YAP localization. STATEMENT OF SIGNIFICANCE: Yes Associated Protein (YAP), a transcription cofactor, has been identified as one of the drivers of cancer progression. High tumor stiffness is attributed to driving YAP to the nucleus, wherein it activates pro-metastatic genes. Here we show, using cancer associated fibroblasts, that YAP translocation to the nucleus depends on the degree of nuclear deformation, irrespective of stiffness. We also identified that perinuclear force induced membrane curvature correlates strongly with YAP nuclear transport. A novel stochastic model of YAP kinetics unveiled a power law relationship between the activation threshold and persistence time of YAP in the nucleus. Overall, this study provides novel insights into the regulatory mechanisms governing YAP dynamics and the probability of activation that is of immense clinical significance.
    Keywords:  Cancer Associated Fibroblast (CAF); Yes Associated Protein (YAP); cell force dynamics; matrix stiffness; nuclear deformation
  3. Commun Biol. 2023 Nov 16. 6(1): 1138
      Oncogenic pathways that drive cancer progression reflect both genetic changes and epigenetic regulation. Here we stratified primary tumors from each of 24 TCGA adult cancer types based on the gene expression patterns of epigenetic factors (epifactors). The tumors for five cancer types (ACC, KIRC, LGG, LIHC, and LUAD) separated into two robust clusters that were better than grade or epithelial-to-mesenchymal transition in predicting clinical outcomes. The majority of epifactors that drove the clustering were also individually prognostic. A pan-cancer machine learning model deploying epifactor expression data for these five cancer types successfully separated the patients into poor and better outcome groups. Single-cell analysis of adult and pediatric tumors revealed that expression patterns associated with poor or worse outcomes were present in individual cells within tumors. Our study provides an epigenetic map of cancer types and lays a foundation for discovering pan-cancer targetable epifactors.
  4. BMC Med Genomics. 2023 Nov 17. 16(1): 295
      Histone deacetylase (HDAC) inhibitors have enormous therapeutic potential as effective epigenetic regulators, and now with the focus on the selective HDAC6 inhibitor in ongoing clinical trials, more advantages over other non-selective pan-HDAC inhibitors are foreseeable. As it is of paramount importance to understand the complex regulatory web of mutual interactions involving epigenetic machinery and non-coding genome in regulating gene expression, herein, we investigated the intriguing interactions between HDAC6-induced lncRNA (LINC00152) and its possible sponge miRNA (hsa-miR-499a-5p) in multiple myeloma.
    Keywords:  Cancer; Epigenetics; Histone deacetylases; Non-coding genome
  5. Sci Rep. 2023 11 13. 13(1): 19740
      Yes-associated protein (YAP) is a transcriptional coactivator that is essential for the malignancy of various cancers. We have previously shown that YAP activity is positively regulated by phosphatidylserine (PS) in recycling endosomes (REs). However, the mechanism by which YAP is activated by PS in REs remains unknown. In the present study, we examined a group of protein phosphatases (11 phosphatases) that we had identified previously as PS-proximity protein candidates. Knockdown experiments of these phosphatases suggested that PPP1R12A, a regulatory subunit of the myosin phosphatase complex, was essential for YAP-dependent proliferation of triple-negative breast cancer MDA-MB-231 cells. Knockdown of PPP1R12A increased the level of phosphorylated YAP, reduced that of YAP in the nucleus, and suppressed the transcription of CTGF (a YAP-regulated gene), reinforcing the role of PPP1R12A in YAP activation. ATP8A1 is a PS-flippase that concentrates PS in the cytosolic leaflet of the RE membrane and positively regulates YAP signalling. In subcellular fractionation experiments using cell lysates, PPP1R12A in control cells was recovered exclusively in the microsomal fraction. In contrast, a fraction of PPP1R12A in ATP8A1-depleted cells was recovered in the cytosolic fraction. Cohort data available from the Cancer Genome Atlas showed that high expression of PPP1R12A, PP1B encoding the catalytic subunit of the myosin phosphatase complex, or ATP8A1 correlated with poor prognosis in breast cancer patients. These results suggest that the "ATP8A1-PS-YAP phosphatase" axis in REs facilitates YAP activation and thus cell proliferation.
  6. Int J Mol Sci. 2023 Oct 30. pii: 15771. [Epub ahead of print]24(21):
      Heterochromatin and euchromatin form different spatial compartments in the interphase nucleus, with heterochromatin being localized mainly at the nuclear periphery. The mechanisms responsible for peripheral localization of heterochromatin are still not fully understood. The nuclear lamina and nuclear pore complexes were obvious candidates for the role of heterochromatin binders. This review is focused on recent studies showing that heterochromatin interactions with the nuclear lamina and nuclear pore complexes maintain its peripheral localization. Differences in chromatin interactions with the nuclear envelope in cell populations and in individual cells are also discussed.
    Keywords:  Elys; LAD; TAD; heterochromatin; lamin; nuclear envelope; nuclear lamina; nuclear periphery; nuclear pore complex; nucleoporin
  7. Mol Cell. 2023 Nov 16. pii: S1097-2765(23)00857-2. [Epub ahead of print]83(22): 4047-4061.e6
      CDK4/6 inhibitors are remarkable anti-cancer drugs that can arrest tumor cells in G1 and induce their senescence while causing only relatively mild toxicities in healthy tissues. How they achieve this mechanistically is unclear. We show here that tumor cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing progression from G1 or inducing genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage, and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize the cells to CDK4/6 inhibition. Together, this demonstrates that cell cycle arrest and oncogenic cell growth is a synthetic lethal combination that is exploited by CDK4/6 inhibitors to induce tumor-specific toxicity.
    Keywords:  CDK4/6; breast cancer; cell cycle; cell growth; chemotherapy; growth factors; oncogenes; p21; p53; replication stress
  8. Aging (Albany NY). 2023 Nov 16. 15
      Mitochondria play a vital role in osteosarcoma. Therefore, the purpose of this study was to investigate the potential role of mitochondrial-related genes (MRGs) in osteosarcoma. Based on 92 differentially expressed MRGs, osteosarcoma samples were divided into two subtypes using the nonnegative matrix factorization (NMF). Ultimately, a univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analysis were performed to construct a prognostic risk model. The single-sample gene set enrichment analysis assessed the immune infiltration characteristics of osteosarcoma patients. Finally, we identified an osteosarcoma biomarker, malonyl-CoA decarboxylase (MLYCD), which showed downregulation. Osteosarcoma cells proliferation, migration, and invasion were effectively inhibited by the overexpression of MLYCD. Our findings will help us to further understand the molecular mechanisms of osteosarcoma and contribute to the discovery of new diagnostic biomarkers and therapeutic targets.
    Keywords:  biomarkers; mitochondrial; molecular subtype; osteosarcoma; prognostic signature