bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2024–10–27
eight papers selected by
Ankita Daiya, OneCell Diagnostics Inc.
  1. Advancements of anticancer agents by targeting the Hippo signalling pathway: biological activity, selectivity, docking analysis, and structure-activity relationship.
  2. Chemomechanical regulation of EZH2 localization controls epithelial-mesenchymal transition.
  3. Emerging roles of cancer-associated histone mutations in genomic instabilities.
  4. Constructing polymorphonuclear cells: chromatin folding shapes nuclear morphology.
  5. The interplay between histone modifications and nuclear lamina in genome regulation.
  6. Protein structural context of cancer mutations reveals molecular mechanisms and candidate driver genes.
  7. Targeting the transcription factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C.
  8. Tetrahedral Framework Nucleic Acid-Loaded Retinoic Acid Promotes Osteosarcoma Stem Cell Clearance.
  1. Mol Divers. 2024 Oct 22.
    Advancements of anticancer agents by targeting the Hippo signalling pathway: biological activity, selectivity, docking analysis, and structure-activity relationship.
    E Haripriya, K Hemalatha, Gurubasavaraja Swamy Purawarga Matada, Rohit Pal, Pronoy Kanti Das, M D Ashadul Sk, S Mounika, M P Viji, I Aayishamma, K R Jayashree.
      The Hippo signalling pathway is prominent and governs cell proliferation and stem cell activity, acting as a growth regulator and tumour suppressor. Defects in Hippo signalling and hyperactivation of its downstream effector's Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play roles in cancer development, implying that pharmacological inhibition of YAP and TAZ activity could be an effective cancer treatment strategy. Conversely, YAP and TAZ can also have beneficial effects in promoting tissue repair and regeneration following damage, therefore their activation may be therapeutically effective in certain instances. Recently, a complex network of intracellular and extracellular signalling mechanisms that affect YAP and TAZ activity has been uncovered. The YAP/TAZ-TEAD interaction leads to tumour development and the protein structure of YAP/TAZ-TEAD includes three interfaces and one hydrophobic pocket. There are clinical and preclinical trial drugs available to inhibit the hippo signalling pathway, but these drugs have moderate to severe side effects, so researchers are in search of novel, potent, and selective hippo signalling pathway inhibitors. In this review, we have discussed the hippo pathway in detail, including its structure, activation, and role in cancer. We have also provided the various inhibitors under clinical and preclinical trials, and advancement of small molecules their detailed docking analysis, structure-activity relationship, and biological activity. We anticipate that the current study will be a helpful resource for researchers.
    Keywords:  Anti-cancer agents; Clinical and preclinical trial drugs; Docking analysis; Hippo signalling pathway; Structure–activity relationship (SAR)
    DOI:  https://doi.org/10.1007/s11030-024-11009-1
  2. J Cell Sci. 2024 Oct 25. pii: jcs.262190. [Epub ahead of print]
    Chemomechanical regulation of EZH2 localization controls epithelial-mesenchymal transition.
    Jessica L Sacco, Zachary T Vaneman, Ava Self, Elix Sumner, Stella Kibinda, Chinmay S Sankhe, Esther W Gomez.
      The methyltransferase enhancer of zeste homolog 2 (EZH2) regulates gene expression and aberrant EZH2 expression and signaling can drive fibrosis and cancer. However, it is not clear how chemical and mechanical signals are integrated to regulate EZH2 and gene expression. We show that culture of cells on stiff matrices in concert with transforming growth factor (TGF)-β1 promotes nuclear localization of EZH2 and an increase in the levels of the corresponding histone modification, H3K27me3, thereby regulating gene expression. EZH2 activity and expression are required for TGFβ1- and stiffness-induced increases in H3K27me3 levels as well as for morphological and gene expression changes associated with epithelial-mesenchymal transition (EMT). Inhibition of Rho associated kinase (ROCK) or myosin II signaling attenuates TGFβ1-induced nuclear localization of EZH2 and decreases H3K27me3 levels in cells cultured on stiff substrata, suggesting that cellular contractility, in concert with a major cancer signaling regulator TGFβ1, modulates EZH2 subcellular localization. These findings provide a contractility-dependent mechanism by which matrix stiffness and TGFβ1 together mediate EZH2 signaling to promote EMT.
    Keywords:  Cell contractility; Histone modification; Matrix stiffness; Methyltransferase; Polycomb repressive complex; Transforming growth factor
    DOI:  https://doi.org/10.1242/jcs.262190
  3. Front Cell Dev Biol. 2024 ;12 1455572
    Emerging roles of cancer-associated histone mutations in genomic instabilities.
    Priyanka Yadav, Ronit Jain, Rajesh Kumar Yadav.
      Epigenetic mechanisms often fuel the quick evolution of cancer cells from normal cells. Mutations or aberrant expressions in the enzymes of DNA methylation, histone post-translational modifications, and chromatin remodellers have been extensively investigated in cancer pathogenesis; however, cancer-associated histone mutants have gained momentum in recent decades. Next-generation sequencing of cancer cells has identified somatic recurrent mutations in all the histones (H3, H4, H2A, H2B, and H1) with different frequencies for various tumour types. Importantly, the well-characterised H3K27M, H3G34R/V, and H3K36M mutations are termed as oncohistone mutants because of their wide roles, from defects in cellular differentiation, transcriptional dysregulation, and perturbed epigenomic profiles to genomic instabilities. Mechanistically, these histone mutants impart their effects on histone modifications and/or on irregular distributions of chromatin complexes. Recent studies have identified the crucial roles of the H3K27M and H3G34R/V mutants in the DNA damage response pathway, but their impacts on chemotherapy and tumour progression remain elusive. In this review, we summarise the recent developments in their functions toward genomic instabilities and tumour progression. Finally, we discuss how such a mechanistic understanding can be harnessed toward the potential treatment of tumours harbouring the H3K27M, H3G34R/V, and H3K36M mutations.
    Keywords:  central nervous system; chromatin; epigenetic mechanism; genomic instability; histone mutation; oncohistone; oncology
    DOI:  https://doi.org/10.3389/fcell.2024.1455572
  4. Trends Immunol. 2024 Oct 21. pii: S1471-4906(24)00220-5. [Epub ahead of print]
    Constructing polymorphonuclear cells: chromatin folding shapes nuclear morphology.
    Cornelis Murre, Indumathi Patta, Shreya Mishra, Ming Hu.
      Immune cell fate decisions are regulated, at least in part, by nuclear architecture. Here, we outline how nuclear architecture instructs mammalian polymorphonuclear cell differentiation. We discuss how in neutrophils loop extrusion mechanisms regulate the expression of genes involved in phagocytosis and shape nuclear morphology. We propose that diminished loop extrusion programs also orchestrate eosinophil and basophil differentiation. We portray a new model in which competitive physical forces, loop extrusion, and phase separation, instruct mononuclear versus polymorphonuclear cell fate decisions. We posit that loop extrusion programs instruct the spatial organization of cytoplasmic organelles, including neutrophil granules, mitochondria, and endoplasmic reticulum. Finally, we suggest that changing loop extrusion programs might allow the engineering of new nuclear shapes and artificial cytoplasmic architectures.
    Keywords:  cytoplasmic architecture; inflammatory gene expression programs; loop extrusion; neutrophil-specific transcription signatures; neutrophils; nuclear architecture; nuclear shape; phagocytosis; phase separation; polymorphonuclear cells
    DOI:  https://doi.org/10.1016/j.it.2024.09.012
  5. J Genet Genomics. 2024 Oct 17. pii: S1673-8527(24)00277-7. [Epub ahead of print]
    The interplay between histone modifications and nuclear lamina in genome regulation.
    Chang Sun, Yanjing Zhao, Liping Guo, Juhui Qiu, Qin Peng.
      Gene expression is regulated by chromatin architecture and epigenetic remodeling in cell homeostasis and pathologies. Histone modifications act as the key factors to modulate the chromatin accessibility. Different histone modifications are strongly associated with the localization of chromatin. Heterochromatin primarily localizes at the nuclear periphery, where it interacts with lamina proteins to suppress gene expression. In this review, we summarize the potential bridges that have regulatory functions of histone modifications in chromatin organization and transcriptional regulation at the nuclear periphery. We use lamina-associated domains (LADs) as examples to elucidate the biological roles of the interactions between histone modifications and nuclear lamina in cell differentiation and development. In the end, we highlight the technologies that are currently used to identify and visualize histone modifications and LADs, which could provide spatiotemporal information for understanding their regulatory functions in gene expression and discovering new targets for diseases.
    Keywords:  Cell differentiation; Chromatin organization; Genome regulation; Histone modifications; Lamina-associated domain; Nuclear lamina
    DOI:  https://doi.org/10.1016/j.jgg.2024.10.005
  6. Cell Rep. 2024 Oct 22. pii: S2211-1247(24)01256-7. [Epub ahead of print]43(11): 114905
    Protein structural context of cancer mutations reveals molecular mechanisms and candidate driver genes.
    Diego Chillón-Pino, Mihaly Badonyi, Colin A Semple, Joseph A Marsh.
      Advances in protein structure determination and modeling allow us to study the structural context of human genetic variants on an unprecedented scale. Here, we analyze millions of cancer-associated missense mutations based on their structural locations and predicted perturbative effects. By considering the collective properties of mutations at the level of individual proteins, we identify distinct patterns associated with tumor suppressors and oncogenes. Tumor suppressors are enriched in structurally damaging mutations, consistent with loss-of-function mechanisms, while oncogene mutations tend to be structurally mild, reflecting selection for gain-of-function driver mutations and against loss-of-function mutations. Although oncogenes are difficult to distinguish from genes with no role in cancer using only structural damage, we find that the three-dimensional clustering of mutations is highly predictive. These observations allow us to identify candidate driver genes and speculate about their molecular roles, which we expect will have general utility in the analysis of cancer sequencing data.
    Keywords:  CP: Cancer; CP: Genomics; Missense mutations; gain-of-function; loss-of-function; oncogenes; protein stability; protein structure; structural bioinformatics; tumor suppressors
    DOI:  https://doi.org/10.1016/j.celrep.2024.114905
  7. EMBO Rep. 2024 Oct 21.
    Targeting the transcription factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C.
    Qian Zheng, Pengfei Li, Yulong Qiang, Jiachen Fan, Yuzhu Xing, Ying Zhang, Fan Yang, Feng Li, Jie Xiong.
      An understanding of the enzymatic and scaffolding functions of epigenetic modifiers is important for the development of epigenetic therapies for cancer. The H3K4me2/3 histone demethylase KDM5C has been shown to regulate transcription. The diverse roles of KDM5C are likely determined by its interacting partners, which are still largely unknown. In this study, we screen for KDM5C-binding proteins and show that YY1 interacts with KDM5C. A synergistic antitumor effect is exerted when both KDM5C and YY1 are depleted, and targeting YY1 appears to be a vulnerability in KDM5C-deficient cancer cells. Mechanistically, KDM5C promotes global YY1 chromatin recruitment, especially at promoters. Moreover, an intact KDM5C JmjC domain but not KDM5C histone demethylase activity is required for KDM5C-mediated YY1 chromatin binding. Transcriptional profiling reveals that dual inhibition of KDM5C and YY1 increases transcriptional repression of cell cycle- and apoptosis-related genes. In summary, our work demonstrates a synthetic lethal interaction between YY1 and KDM5C and suggests combination therapies for cancer treatments.
    Keywords:  Cancer Therapy; Chromatin Recruitment; KDM5C; Promoter; YY1
    DOI:  https://doi.org/10.1038/s44319-024-00290-8
  8. ACS Appl Mater Interfaces. 2024 Oct 19.
    Tetrahedral Framework Nucleic Acid-Loaded Retinoic Acid Promotes Osteosarcoma Stem Cell Clearance.
    Weifei Zhang, Mengqing Li, Zhen Zhao, Jiangshan Xu, Junlin Liu, Pin Feng, Bin Zhang, Zhangheng Huang, Qing-Quan Kong, Yunfeng Lin.
      Metastatic osteosarcoma is a commonly seen malignant tumor in adolescents, with a five year survival rate of approximately 20% and a lack of treatment options. Osteosarcoma cancer stem cells are considered to be important drivers of the metastasis of osteosarcoma, and therefore their clearance is considered a promising strategy for treating metastatic osteosarcoma. In the relevant literature, retinoic acid (ATRA) is considered effective for eliminating osteosarcoma stem cells, but it has some inherent disadvantages, including poor solubility, difficulty in entering cells, and structural instability. Tetrahedral framework nucleic acids (tFNAs) are a type of nanoparticles that can carry small-molecule drugs into cells to exert therapeutic effects. Therefore, we designed and synthesized a nanoparticle named T-ATRA by using tFNAs to load ATRA and studied its effect in a nude mouse model. T-ATRA is more effective than ATRA in the clearance of osteosarcoma stem cells and in inhibiting osteosarcoma cell metastasis via the Wnt signaling pathway, thus prolonging the survival time of nude mice with osteosarcoma.
    Keywords:  ATRA; Wnt signaling pathway; osteosarcoma stem cell; retinoic acid; tetrahedral framework nucleic acid
    DOI:  https://doi.org/10.1021/acsami.4c14440
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