bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023–09–10
nine papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer.
  2. Non-canonical functions of EZH2 in cancer.
  3. Mitochondrial Factors in the Cell Nucleus.
  4. p53-regulated lncRNAs in cancers: from proliferation and metastasis to therapy.
  5. ChIP-chip data for identifying target genes and consensus binding sequences of mutant p53 in MDA-MB-468 breast cancer cells.
  6. A non-canonical role: The Hippo pathway regulator MAP4K2 controls autophagy and cell survival upon energy stress.
  7. Dynamic Phosphorylation of G9a Regulates its Repressive Activity on Chromatin Accessibility and Mitotic Progression.
  8. Protein Condensates and Protein Aggregates: In Vitro, in the Cell, and In Silico.
  9. ChromGene: gene-based modeling of epigenomic data.
  1. iScience. 2023 Sep 15. 26(9): 107630
    Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer.
    Ahmed H Ghobashi, Truc T Vuong, Jane W Kimani, Christopher A Ladaika, Peter C Hollenhorst, Heather M O'Hagan.
      Colorectal cancer (CRC) develops in part through the deregulation of different signaling pathways, including activation of the WNT/β-catenin and PI3K/AKT pathways. Additionally, the lysine methyltransferase enhancer of zeste homologue 2 (EZH2) is commonly overexpressed in CRC. EZH2 canonically represses gene transcription by trimethylating lysine 27 of histone H3, but also has non-histone substrates. Here, we demonstrated that in CRC, active AKT phosphorylated EZH2 on serine 21. Phosphorylation of EZH2 by AKT induced EZH2 to interact with and methylate β-catenin at lysine 49, which increased β-catenin's binding to the chromatin. Additionally, EZH2-mediated β-catenin trimethylation induced β-catenin to interact with TCF1 and RNA polymerase II and resulted in dramatic gains in genomic regions with β-catenin occupancy. EZH2 catalytic inhibition decreased stemness but increased migratory phenotypes of CRC cells with active AKT. Overall, we demonstrated that EZH2 modulates AKT-induced changes in gene expression through the AKT/EZH2/β-catenin axis in CRC.
    Keywords:  Cancer; Epigenetics; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107630
  2. Front Oncol. 2023 ;13 1233953
    Non-canonical functions of EZH2 in cancer.
    Sarah M Zimmerman, Phyo Nay Lin, George P Souroullas.
      Mutations in chromatin modifying genes frequently occur in many kinds of cancer. Most mechanistic studies focus on their canonical functions, while therapeutic approaches target their enzymatic activity. Recent studies, however, demonstrate that non-canonical functions of chromatin modifiers may be equally important and therapeutically actionable in different types of cancer. One epigenetic regulator that demonstrates such a dual role in cancer is the histone methyltransferase EZH2. EZH2 is a core component of the polycomb repressive complex 2 (PRC2), which plays a crucial role in cell identity, differentiation, proliferation, stemness and plasticity. While much of the regulatory functions and oncogenic activity of EZH2 have been attributed to its canonical, enzymatic activity of methylating lysine 27 on histone 3 (H3K27me3), a repressive chromatin mark, recent studies suggest that non-canonical functions that are independent of H3K27me3 also contribute towards the oncogenic activity of EZH2. Contrary to PRC2's canonical repressive activity, mediated by H3K27me3, outside of the complex EZH2 can directly interact with transcription factors and oncogenes to activate gene expression. A more focused investigation into these non-canonical interactions of EZH2 and other epigenetic/chromatin regulators may uncover new and more effective therapeutic strategies. Here, we summarize major findings on the non-canonical functions of EZH2 and how they are related to different aspects of carcinogenesis.
    Keywords:  EZH2; H3K27me3; cancer; non-canonical; oncogene; tumor suppressor
    DOI:  https://doi.org/10.3389/fonc.2023.1233953
  3. Int J Mol Sci. 2023 Sep 04. pii: 13656. [Epub ahead of print]24(17):
    Mitochondrial Factors in the Cell Nucleus.
    Katiuska González-Arzola, Antonio Díaz-Quintana.
      The origin of eukaryotic organisms involved the integration of mitochondria into the ancestor cell, with a massive gene transfer from the original proteobacterium to the host nucleus. Thus, mitochondrial performance relies on a mosaic of nuclear gene products from a variety of genomes. The concerted regulation of their synthesis is necessary for metabolic housekeeping and stress response. This governance involves crosstalk between mitochondrial, cytoplasmic, and nuclear factors. While anterograde and retrograde regulation preserve mitochondrial homeostasis, the mitochondria can modulate a wide set of nuclear genes in response to an extensive variety of conditions, whose response mechanisms often merge. In this review, we summarise how mitochondrial metabolites and proteins-encoded either in the nucleus or in the organelle-target the cell nucleus and exert different actions modulating gene expression and the chromatin state, or even causing DNA fragmentation in response to common stress conditions, such as hypoxia, oxidative stress, unfolded protein stress, and DNA damage.
    Keywords:  DNA damage; hypoxia; mito-nuclear crosstalk; oxidative stress; stress response; unfolded stress response
    DOI:  https://doi.org/10.3390/ijms241713656
  4. Cancer Gene Ther. 2023 Sep 07.
    p53-regulated lncRNAs in cancers: from proliferation and metastasis to therapy.
    Kaixin Yang, Yinan Xiao, Linghui Zhong, Wenyang Zhang, Peng Wang, Yaru Ren, Lei Shi.
      Long non-coding RNAs (lncRNAs) have been identified as master gene regulators through various mechanisms such as transcription, translation, protein modification and RNA-protein complexes. LncRNA dysregulation is frequently associated with a variety of biological functions and human diseases including cancer. The p53 network is a key tumor-suppressive mechanism that transcriptionally activates target genes to suppress cellular proliferation in human malignancies. Recent research indicates that lncRNAs play an important role in the p53 signaling pathway. In this review, we summarize the current knowledge of lncRNAs in p53-relevant functions and provide an overview of how these altered lncRNAs contribute to tumor initiation and progression. We also discuss the association between lncRNA and up- or downstream genes of p53. These findings imply that lncRNAs can help identify cellular vulnerabilities that may prove to be promising potential biomarkers and therapeutic targets for cancer treatment.
    DOI:  https://doi.org/10.1038/s41417-023-00662-7
  5. Data Brief. 2023 Oct;50 109499
    ChIP-chip data for identifying target genes and consensus binding sequences of mutant p53 in MDA-MB-468 breast cancer cells.
    Mai Nhu Uyen Le, Yichong Ning, Jianlin Zhou.
      The tumor suppressor p53 exerts its role mainly as a transcription factor. The TP53 gene, which encodes the p53 protein, is the most commonly mutated gene in human cancers, particularly triple negative breast cancer (TNBC). Variations in the TP53 gene occur mainly in exons 5-8 and result in missense mutations in the DNA-binding domain of the p53 protein that alter DNA binding specificity. To identify the target genes of mutant p53, we performed chromatin immunoprecipitation followed by DNA microarray (ChIP-chip). Briefly, the TNBC cell line MDA-MB-468 containing the endogenous p53-R273H mutation (the arginine residue at position 273 is mutated to a histidine) was cross-linked with 1% formaldehyde and ultrasonically sheared to generate chromatin fragments in a range of 200∼1000 bp. An aliquot of the sheared chromatin was kept as input, and the other chromatin was precipitated with a p53 monoclonal antibody. DNA was purified from the precipitated chromatin and the unprecipitated chromatin (i.e., input), amplified, and labeled with Cy5 (ChIP DNA) or Cy3 (input DNA). Cy5- and Cy3-labeled DNA samples were cohybridized with the NimbleGen Human ChIP-chip 2.1 M Deluxe Promoter Array. The raw and analyzed data are described in this article. They are useful for identifying target genes and consensus binding motifs of the p53 R273H mutant and for further clarifying the molecular mechanism underlying the oncogenic activity of the p53 mutant.
    Keywords:  Chromatin immunoprecipitation (ChIP); DNA binding motif; DNA microarray; TP53; Transcription factor
    DOI:  https://doi.org/10.1016/j.dib.2023.109499
  6. Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00657-3. [Epub ahead of print]83(17): 3043-3045
    A non-canonical role: The Hippo pathway regulator MAP4K2 controls autophagy and cell survival upon energy stress.
    Anne Schreiber.
      In this issue, Seo et al.1 report a non-canonical function of the Hippo kinase MAP4K2 in energy stress response by regulating autophagy and cell survival, with relevance and therapeutic potential for head and neck cancer treatment.
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.020
  7. Adv Sci (Weinh). 2023 Sep 03. e2303224
    Dynamic Phosphorylation of G9a Regulates its Repressive Activity on Chromatin Accessibility and Mitotic Progression.
    Qizhi Geng, Yue-Yu Kong, Weizhe Li, Jianhao Zhang, Haoli Ma, Yuhang Zhang, Lin-Tai Da, Yan Zhao, Hai-Ning Du.
      Phosphorylation of Ser10 of histone H3 (H3S10p), together with the adjacent methylation of Lys9 (H3K9me), has been proposed to function as a 'phospho-methyl switch' to regulate mitotic chromatin architecture. Despite of immense understanding of the roles of H3S10 phosphorylation, how H3K9me2 are dynamically regulated during mitosis is poorly understood. Here, it is identified that Plk1 kinase phosphorylates the H3K9me1/2 methyltransferase G9a/EHMT2 at Thr1045 (pT1045) during early mitosis, which attenuates its catalytic activity toward H3K9me2. Cells bearing Thr1045 phosphomimic mutant of G9a (T1045E) show decreased H3K9me2 levels, increased chromatin accessibility, and delayed mitotic progression. By contrast, dephosphorylation of pT1045 during late mitosis by the protein phosphatase PPP2CB reactivates G9a activity and upregulates H3K9me2 levels, correlated with decreased levels of H3S10p. Therefore, the results provide a mechanistic explanation of the essential of a 'phospho-methyl switch' and highlight the importance of Plk1 and PPP2CB-mediated dynamic regulation of G9a activity in chromatin organization and mitotic progression.
    Keywords:  G9a phosphorylation; Plk1, PPP2CB; chromatin accessibility; mitotic progression
    DOI:  https://doi.org/10.1002/advs.202303224
  8. Front Biosci (Landmark Ed). 2023 Aug 28. 28(8): 183
    Protein Condensates and Protein Aggregates: In Vitro, in the Cell, and In Silico.
    Katja Venko, Eva Žerovnik.
      Similar to other polypeptides and electrolytes, proteins undergo phase transitions, obeying physicochemical laws. They can undergo liquid-to-gel and liquid-to-liquid phase transitions. Intrinsically disordered proteins are particularly susceptible to phase separation. After a general introduction, the principles of in vitro studies of protein folding, aggregation, and condensation are described. Numerous recent and older studies have confirmed that the process of liquid-liquid phase separation (LLPS) leads to various condensed bodies in cells, which is one way cells manage stress. We review what is known about protein aggregation and condensation in the cell, notwithstanding the protective and pathological roles of protein aggregates. This includes membrane-less organelles and cytotoxicity of the prefibrillar oligomers of amyloid-forming proteins. We then describe and evaluate bioinformatic (in silico) methods for predicting protein aggregation-prone regions of proteins that form amyloids, prions, and condensates.
    Keywords:  LLPS; amyloid; intrinsically disordered proteins (IDPs); membrane-less organelles; neurodegeneration; prediction by in silico methods; prion; protein aggregation; protein condensation
    DOI:  https://doi.org/10.31083/j.fbl2808183
  9. Genome Biol. 2023 Sep 07. 24(1): 203
    ChromGene: gene-based modeling of epigenomic data.
    Artur Jaroszewicz, Jason Ernst.
      Various computational approaches have been developed to annotate epigenomes on a per-position basis by modeling combinatorial and spatial patterns within epigenomic data. However, such annotations are less suitable for gene-based analyses. We present ChromGene, a method based on a mixture of learned hidden Markov models, to annotate genes based on multiple epigenomic maps across the gene body and flanks. We provide ChromGene assignments for over 100 cell and tissue types. We characterize the mixture components in terms of gene expression, constraint, and other gene annotations. The ChromGene method and annotations will provide a useful resource for gene-based epigenomic analyses.
    Keywords:  Chromatin; Epigenomics; Hidden Markov models; Histone modifications; Machine learning
    DOI:  https://doi.org/10.1186/s13059-023-03041-5
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