bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022–07–31
six papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Transcriptional Regulation of the Hippo Pathway: Current Understanding and Insights from Single-Cell Technologies.
  2. The Role of HDACs in the Response of Cancer Cells to Cellular Stress and the Potential for Therapeutic Intervention.
  3. Optogenetic control of YAP cellular localisation and function.
  4. Pseudogenes and Liquid Phase Separation in Epigenetic Expression.
  5. HSF1 phosphorylation establishes an active chromatin state via the TRRAP-TIP60 complex and promotes tumorigenesis.
  6. Forced Overexpression of Signal Transducer and Activator of Transcription 3 (STAT3) Activates Yes-Associated Protein (YAP) Expression and Increases the Invasion and Proliferation Abilities of Small Cell Lung Cancer (SCLC) Cells.
  1. Cells. 2022 Jul 17. pii: 2225. [Epub ahead of print]11(14):
    Transcriptional Regulation of the Hippo Pathway: Current Understanding and Insights from Single-Cell Technologies.
    Sayantanee Paul, Shiqi Xie, Xiaosai Yao, Anwesha Dey.
      The Hippo pathway regulates tissue homeostasis in normal development and drives oncogenic processes. In this review, we extensively discuss how YAP/TAZ/TEAD cooperate with other master transcription factors and epigenetic cofactors to orchestrate a broad spectrum of transcriptional responses. Even though these responses are often context- and lineage-specific, we do not have a good understanding of how such precise and specific transcriptional control is achieved-whether they are driven by differences in TEAD paralogs, or recruitment of cofactors to tissue-specific enhancers. We believe that emerging single-cell technologies would enable a granular understanding of how the Hippo pathway influences cell fate and drives oncogenic processes, ultimately allowing us to design better pharmacological agents against TEADs and identify robust pharmacodynamics markers of Hippo pathway inhibition.
    Keywords:  Hippo signaling; TEAD; single cell technologies; transcriptional regulation
    DOI:  https://doi.org/10.3390/cells11142225
  2. Int J Mol Sci. 2022 Jul 24. pii: 8141. [Epub ahead of print]23(15):
    The Role of HDACs in the Response of Cancer Cells to Cellular Stress and the Potential for Therapeutic Intervention.
    Rahma K Alseksek, Wafaa S Ramadan, Ekram Saleh, Raafat El-Awady.
      Throughout the process of carcinogenesis, cancer cells develop intricate networks to adapt to a variety of stressful conditions including DNA damage, nutrient deprivation, and hypoxia. These molecular networks encounter genomic instability and mutations coupled with changes in the gene expression programs due to genetic and epigenetic alterations. Histone deacetylases (HDACs) are important modulators of the epigenetic constitution of cancer cells. It has become increasingly known that HDACs have the capacity to regulate various cellular systems through the deacetylation of histone and bounteous nonhistone proteins that are rooted in complex pathways in cancer cells to evade death pathways and immune surveillance. Elucidation of the signaling pathways involved in the adaptive responses to cellular stress and the role of HDACs may lead to the development of novel therapeutic agents. In this article, we overview the dominant stress types including metabolic, oxidative, genotoxic, and proteotoxic stress imposed on cancer cells in the context of HDACs, which guide stress adaptation responses. Next, we expose a closer view on the therapeutic interventions and clinical trials that involve HDACs inhibitors, in addition to highlighting the impact of using HDAC inhibitors in combination with stress-inducing agents for the management of cancer and to overcome the resistance to current cancer therapy.
    Keywords:  HDAC inhibitors; HDACs; cellular stress; immune modulation
    DOI:  https://doi.org/10.3390/ijms23158141
  3. EMBO Rep. 2022 Jul 25. e54401
    Optogenetic control of YAP cellular localisation and function.
    Pearlyn J Y Toh, Jason K H Lai, Anke Hermann, Olivier Destaing, Michael P Sheetz, Marius Sudol, Timothy E Saunders.
      YAP, an effector of the Hippo signalling pathway, promotes organ growth and regeneration. Prolonged YAP activation results in uncontrolled proliferation and cancer. Therefore, exogenous regulation of YAP activity has potential translational applications. We present a versatile optogenetic construct (optoYAP) for manipulating YAP localisation, and consequently its activity and function. We attach a LOV2 domain that photocages a nuclear localisation signal (NLS) to the N-terminus of YAP. In 488 nm light, the LOV2 domain unfolds, exposing the NLS, which shuttles optoYAP into the nucleus. Nuclear import of optoYAP is reversible and tuneable by light intensity. In cell culture, activated optoYAP promotes YAP target gene expression and cell proliferation. Similarly, optofYap can be used in zebrafish embryos to modulate target genes. We demonstrate that optoYAP can override a cell's response to substrate stiffness to generate anchorage-independent growth. OptoYAP is functional in both cell culture and in vivo, providing a powerful tool to address basic research questions and therapeutic applications in regeneration and disease.
    Keywords:  YAP; cell proliferation; optogenetics; spatiotemporal dynamics; zebrafish
    DOI:  https://doi.org/10.15252/embr.202154401
  4. Front Oncol. 2022 ;12 912282
    Pseudogenes and Liquid Phase Separation in Epigenetic Expression.
    Bernard Nsengimana, Faiz Ali Khan, Usman Ayub Awan, Dandan Wang, Na Fang, Wenqiang Wei, Weijuan Zhang, Shaoping Ji.
      Pseudogenes have been considered as non-functional genes. However, peptides and long non-coding RNAs produced by pseudogenes are expressed in different tumors. Moreover, the dysregulation of pseudogenes is associated with cancer, and their expressions are higher in tumors compared to normal tissues. Recent studies show that pseudogenes can influence the liquid phase condensates formation. Liquid phase separation involves regulating different epigenetic stages, including transcription, chromatin organization, 3D DNA structure, splicing, and post-transcription modifications like m6A. Several membrane-less organelles, formed through the liquid phase separate, are also involved in the epigenetic regulation, and their defects are associated with cancer development. However, the association between pseudogenes and liquid phase separation remains unrevealed. The current study sought to investigate the relationship between pseudogenes and liquid phase separation in cancer development, as well as their therapeutic implications.
    Keywords:  RNA modification; cancer; epigenetic; liquid phase separation; pseudogenes
    DOI:  https://doi.org/10.3389/fonc.2022.912282
  5. Nat Commun. 2022 Jul 29. 13(1): 4355
    HSF1 phosphorylation establishes an active chromatin state via the TRRAP-TIP60 complex and promotes tumorigenesis.
    Mitsuaki Fujimoto, Ryosuke Takii, Masaki Matsumoto, Mariko Okada, Keiich I Nakayama, Ryuichiro Nakato, Katsunori Fujiki, Katsuhiko Shirahige, Akira Nakai.
      Transcriptional regulation by RNA polymerase II is associated with changes in chromatin structure. Activated and promoter-bound heat shock transcription factor 1 (HSF1) recruits transcriptional co-activators, including histone-modifying enzymes; however, the mechanisms underlying chromatin opening remain unclear. Here, we demonstrate that HSF1 recruits the TRRAP-TIP60 acetyltransferase complex in HSP72 promoter during heat shock in a manner dependent on phosphorylation of HSF1-S419. TRIM33, a bromodomain-containing ubiquitin ligase, is then recruited to the promoter by interactions with HSF1 and a TIP60-mediated acetylation mark, and cooperates with the related factor TRIM24 for mono-ubiquitination of histone H2B on K120. These changes in histone modifications are triggered by phosphorylation of HSF1-S419 via PLK1, and stabilize the HSF1-transcription complex in HSP72 promoter. Furthermore, HSF1-S419 phosphorylation is constitutively enhanced in and promotes proliferation of melanoma cells. Our results provide mechanisms for HSF1 phosphorylation-dependent establishment of an active chromatin status, which is important for tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-022-32034-4
  6. Biomedicines. 2022 Jul 14. pii: 1704. [Epub ahead of print]10(7):
    Forced Overexpression of Signal Transducer and Activator of Transcription 3 (STAT3) Activates Yes-Associated Protein (YAP) Expression and Increases the Invasion and Proliferation Abilities of Small Cell Lung Cancer (SCLC) Cells.
    Ping-Chih Hsu, Jhy-Ming Li, Cheng-Ta Yang.
       BACKGROUND: We sought to investigate the interaction between signal transducer and activator of transcription 3 (STAT3) and the Yes-associated protein (YAP) signaling pathway in human small cell lung cancer (SCLC) cells.
    METHODS: The STAT3-overexpressing SCLC cell lines H146 and H446 were established by plasmid DNA transfection for in vitro and in vivo experiments.
    RESULTS: Overexpression of STAT3 increased YAP protein expression in H146 and H446 cells. STAT3 overexpression significantly increased YAP mRNA expression and the mRNA expression of the YAP signaling downstream genes CTGF and CYR61 in H146 and H446 cells (p < 0.05). We showed that STAT3 overexpression promoted EMT (epithelial-mesenchymal transition) with increased matrix metalloproteinase (MMP)-2 and MMP9 expression. Transwell assays showed that STAT3 overexpression increased the invasion ability of H146 and H446 cells. In addition, STAT3-overexpressing H146 cells grew significantly more rapidly than control H146 cells in the xenograft mouse model (p < 0.05). Immunohistochemistry (IHC) staining and Western blotting (WB) showed that STAT3-overexpressing H146 tumors had increased p-STAT3 and YAP staining and protein expression compared with control tumors. Increased EMT was also observed in STAT3-overexpressed xenograft tumors.
    CONCLUSIONS: The results of our study suggest that the overexpression of STAT3 promotes SCLC EMT, invasion, and proliferation through the activation of the YAP signaling pathway.
    Keywords:  Hippo signaling; epithelial–mesenchymal transition (EMT); proliferation; signal transducer and activator of transcription 3 (STAT3); small cell lung cancer; yes-associated protein (YAP)
    DOI:  https://doi.org/10.3390/biomedicines10071704
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