bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023–12–17
seven papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Advances in bi-directional relationships for EZH2 and oxidative stress.
  2. New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer.
  3. Cell stretching activates an ATM mechano-transduction pathway that remodels cytoskeleton and chromatin.
  4. YAP localization mediates mechanical adaptation of human cancer cells during extravasation in vivo.
  5. Polycomb protein binding and looping mediated by Polycomb Response Elements in the ON transcriptional state.
  6. Current HDAC Inhibitors in Clinical Trials.
  7. Metabolic challengers selecting tumor-persistent cells.
  1. Exp Cell Res. 2023 Dec 07. pii: S0014-4827(23)00427-5. [Epub ahead of print] 113876
    Advances in bi-directional relationships for EZH2 and oxidative stress.
    Heng Qin, Chang Liu, Changqing Li, Chencheng Feng, Bo Huang.
      Over the past two decades, polycomb repressive complex 2(PRC2) has emerged as a vital repressive complex in overall cell fate determination. In mammals, enhancer of zeste homolog 2 (EHZ2), which is the core component of PRC2, has also been recognized as an important regulator of inflammatory, redox, tumorigenesis and damage repair signalling networks. To exert these effects, EZH2 must regulate target genes epigenetically or interact directly with other gene expression-regulating factors, such as LncRNAs and microRNAs. Our review provides a comprehensive summary of research advances, discoveries and trends regarding the regulatory mechanisms between EZH2 and reactive oxygen species (ROS). First, we outline novel findings about how EZH2 regulates the generation of ROS at the molecular level. Then, we summarize how oxidative stress controls EHZ2 alteration (upregulation, downregulation, or phosphorylation) via various molecules and signalling pathways. Finally, we address why EZH2 and oxidative stress have an undefined relationship and provide potential future research ideas.
    Keywords:  EZH2; Reactive oxygen species; Signalling pathway
    DOI:  https://doi.org/10.1016/j.yexcr.2023.113876
  2. Cancers (Basel). 2023 Nov 21. pii: 5497. [Epub ahead of print]15(23):
    New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer.
    Yang Zhao, Marisela Sheldon, Yutong Sun, Li Ma.
      The Hippo pathway is conserved across species. Key mammalian Hippo pathway kinases, including MST1/2 and LATS1/2, inhibit cellular growth by inactivating the TEAD coactivators, YAP, and TAZ. Extensive research has illuminated the roles of Hippo signaling in cancer, development, and regeneration. Notably, dysregulation of Hippo pathway components not only contributes to tumor growth and metastasis, but also renders tumors resistant to therapies. This review delves into recent research on YAP/TAZ-TEAD-mediated gene regulation and biological processes in cancer. We focus on several key areas: newly identified molecular patterns of YAP/TAZ activation, emerging mechanisms that contribute to metastasis and cancer therapy resistance, unexpected roles in tumor suppression, and advances in therapeutic strategies targeting this pathway. Moreover, we provide an updated view of YAP/TAZ's biological functions, discuss ongoing controversies, and offer perspectives on specific debated topics in this rapidly evolving field.
    Keywords:  TAZ; TEAD; YAP; cancer therapy; gene regulation; metastasis
    DOI:  https://doi.org/10.3390/cancers15235497
  3. Cell Rep. 2023 Dec 11. pii: S2211-1247(23)01567-X. [Epub ahead of print]42(12): 113555
    Cell stretching activates an ATM mechano-transduction pathway that remodels cytoskeleton and chromatin.
    Giulia Bastianello, Giancarlo Porcella, Galina V Beznoussenko, Gururaj Kidiyoor, Flora Ascione, Qingsen Li, Angela Cattaneo, Vittoria Matafora, Andrea Disanza, Micaela Quarto, Alexander A Mironov, Amanda Oldani, Sara Barozzi, Angela Bachi, Vincenzo Costanzo, Giorgio Scita, Marco Foiani.
      Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) DNA damage response (DDR) kinases contain elastic domains. ATM also responds to reactive oxygen species (ROS) and ATR to nuclear mechanical stress. Mre11 mediates ATM activation following DNA damage; ATM mutations cause ataxia telangiectasia (A-T). Here, using in vivo imaging, electron microscopy, proteomic, and mechano-biology approaches, we study how ATM responds to mechanical stress. We report that cytoskeleton and ROS, but not Mre11, mediate ATM activation following cell deformation. ATM deficiency causes hyper-stiffness, stress fiber accumulation, Yes-associated protein (YAP) nuclear enrichment, plasma and nuclear membrane alterations during interstitial migration, and H3 hyper-methylation. ATM locates to the actin cytoskeleton and, following cytoskeleton stress, promotes phosphorylation of key cytoskeleton and chromatin regulators. Our data contribute to explain some clinical features of patients with A-T and pinpoint the existence of an integrated mechano-response in which ATM and ATR have distinct roles unrelated to their canonical DDR functions.
    Keywords:  ATM and ATR; CP: Cell biology; CP: Molecular biology; DNA damage response; ROS; ataxia telangiectasia; cell stretching; checkpoints; chromatin; cytoskeleton; interstitial migration; mechanical stress
    DOI:  https://doi.org/10.1016/j.celrep.2023.113555
  4. bioRxiv. 2023 Nov 16. pii: 2023.11.14.567015. [Epub ahead of print]
    YAP localization mediates mechanical adaptation of human cancer cells during extravasation in vivo.
    Woong Young So, Claudia S Wong, Udochi F Azubuike, Colin D Paul, Paniz Rezvan Sangsari, Patricia B Gordon, Hyeyeon Gong, Tapan K Maity, Perry Lim, Zhilin Yang, Christian A Haryanto, Eric Batchelor, Lisa M Jenkins, Nicole Y Morgan, Kandice Tanner.
      Biophysical profiling of primary tumors has revealed that individual tumor cells fall along a highly heterogeneous continuum of mechanical phenotypes. One idea is that a subset of tumor cells is "softer" to facilitate detachment and escape from the primary site, a step required to initiate metastasis. However, it has also been postulated that cells must be able to deform and generate sufficient force to exit into distant sites. Here, we aimed to dissect the mechanical changes that occur during extravasation and organ colonization. Using multiplexed methods of intravital microscopy and optical tweezer based active microrheology, we obtained longitudinal images and mechanical profiles of cells during organ colonization in vivo . We determined that cells were softer, more liquid like upon exit of the vasculature but stiffened and became more solid like once in the new organ microenvironment. We also determined that a YAP mediated mechanogenotype influenced the global dissemination in our in vivo and in vitro models and that reducing mechanical heterogeneity could reduce extravasation. Moreover, our high throughput analysis of mechanical phenotypes of patient samples revealed that this mechanics was in part regulated by the external hydrodynamic forces that the cancer cells experienced within capillary mimetics. Our findings indicate that disseminated cancer cells can keep mutating with a continuum landscape of mechano-phenotypes, governed by the YAP-mediated mechanosensing of hydrodynamic flow.
    DOI:  https://doi.org/10.1101/2023.11.14.567015
  5. bioRxiv. 2023 Nov 04. pii: 2023.11.02.565256. [Epub ahead of print]
    Polycomb protein binding and looping mediated by Polycomb Response Elements in the ON transcriptional state.
    J Lesley Brown, Liangliang Zhang, Pedro P Rocha, Judith A Kassis, Ming-An Sun.
      Polycomb group proteins (PcG) mediate epigenetic silencing of important developmental genes and other targets. In Drosophila, canonical PcG-target genes contain Polycomb Response Elements (PREs) that recruit PcG protein complexes including PRC2 that tri- methylates H3K27 forming large H3K27me3 domains. In the OFF transcriptional state, PREs loop with each other and this looping strengthens silencing. Here we address the question of what PcG proteins bind to PREs when canonical PcG target genes are expressed, and whether PREs loop when these genes are ON. Our data show that the answer to this question is PRE-specific but general conclusions can be made. First, within a PcG-target gene, some regulatory DNA can remain covered with H3K27me3 and PcG proteins remain bound to PREs in these regions. Second, when PREs are within H3K27ac domains, PcG- binding decreases, however, this depends on the protein and PRE. The DNA binding protein GAF, and the PcG protein Ph remain at PREs even when other PcG proteins are greatly depleted. In the ON state, PREs can still loop with each other, but also form loops with presumptive enhancers. These data support the model that, in addition to their role in PcG silencing, PREs can act as "promoter-tethering elements" mediating interactions between promoter proximal PREs and distant enhancers.
    DOI:  https://doi.org/10.1101/2023.11.02.565256
  6. Chimia (Aarau). 2022 May 25. 76(5): 448-453
    Current HDAC Inhibitors in Clinical Trials.
    Elisabetta Di Bello, Beatrice Noce, Rossella Fioravanti, Antonello Mai.
      Epigenetic modifications in eukaryotic biological pathways can lead to the up- or downregulation of regulatory proteins contributing to disease onset and progression. In the last three decades, histone deacetylases (HDACs) are among the most studied epigenetic targets. In fact, aberrant HDAC expression is associated with numerous types of cancer and neurodegenerative disorders, making HDACs promising molecular targets for the design of new drugs. Many HDAC inhibitors (HDACi) are currently in clinical evaluation for various types of cancer, and some of them reached the market after approval by the Food and Drug Administration (FDA). The present review summarizes the various HDAC classes and relative isoforms. Then we discuss different class or isoform-selective HDACi with a strong emphasis on late-stage preclinical candidates and drugs in clinical studies. Last but not least, we shed light on the pharmacokinetic challenges and future directions in HDACi design.
    Keywords:  Cancer; Clinical studies; Epigenetics; Histone deacetylases
    DOI:  https://doi.org/10.2533/chimia.2022.448
  7. Trends Endocrinol Metab. 2023 Dec 09. pii: S1043-2760(23)00244-8. [Epub ahead of print]
    Metabolic challengers selecting tumor-persistent cells.
    Caterina Mancini, Giulia Lori, Erica Pranzini, Maria Letizia Taddei.
      Resistance to anticancer therapy still represents one of the main obstacles to cancer treatment. Numerous components of the tumor microenvironment (TME) contribute significantly to the acquisition of drug resistance. Microenvironmental pressures arising during cancer evolution foster tumor heterogeneity (TH) and facilitate the emergence of drug-resistant clones. In particular, metabolic pressures arising in the TME may favor epigenetic adaptations supporting the acquisition of persistence features in tumor cells. Tumor-persistent cells (TPCs) are characterized by high phenotypic and metabolic plasticity, representing a noticeable advantage in chemo- and radio-resistance. Understanding the crosslink between the evolution of metabolic pressures in the TME, epigenetics, and TPC evolution is significant for developing novel therapeutic strategies specifically targeting TPC vulnerabilities to overcome drug resistance.
    Keywords:  epigenetics; metabolism; therapy resistance; tumor microenvironment; tumor-persistent cells
    DOI:  https://doi.org/10.1016/j.tem.2023.11.005
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