bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022–10–09
eight papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Capicua suppresses YAP1 to limit tumorigenesis and maintain drug sensitivity in human cancer.
  2. Computational methods to explore chromatin state dynamics.
  3. Characterization of KDM5 lysine demethylase family substrate preference and identification of novel substrates.
  4. Variant calling enhances the identification of cancer cells in single-cell RNA sequencing data.
  5. Nuclear position modulates long-range chromatin interactions.
  6. The synergistic interaction landscape of chromatin regulators reveals their epigenetic regulation mechanisms across five cancer cell lines.
  7. DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities.
  8. The hypoxia-related signature predicts prognosis, pyroptosis and drug sensitivity of osteosarcoma.
  1. Cell Rep. 2022 Oct 04. pii: S2211-1247(22)01284-0. [Epub ahead of print]41(1): 111443
    Capicua suppresses YAP1 to limit tumorigenesis and maintain drug sensitivity in human cancer.
    Ji Won Kim, Cuyler Luck, Wei Wu, Rovingaile Kriska Ponce, Yone Kawe Lin, Nehal Gupta, Ross A Okimoto.
      Inactivation of Capicua (CIC) or upregulation of yes-associated protein 1, YAP1, leads to broad RAS-RAF-MEK-ERK inhibitor resistance and tumor progression in multiple human cancers. Despite these shared malignant phenotypes, it remains unclear whether CIC and YAP1 are mechanistically linked. Here, we show that the ERK-regulated transcription factor CIC can directly repress YAP1 expression through non-consensus GGAAGGAA DNA-binding motifs in a proximal YAP1 regulatory element. Through binding at GGAA repeats, CIC regulates YAP1 transcriptional output in both normal and human cancer cells. Silencing YAP1 in CIC-deficient cells restores MAPK inhibitor sensitivity and suppresses tumor growth. Thus, we uncover a molecular link between the MAPK-ERK effector CIC and YAP1 in human cells and established YAP inhibition as a strategy to target CIC-deficient cancers.
    Keywords:  CIC; CP: Cancer; CP: Molecular biology; Capicua; MAPK inhibitor resistance; YAP1
    DOI:  https://doi.org/10.1016/j.celrep.2022.111443
  2. Brief Bioinform. 2022 Oct 07. pii: bbac439. [Epub ahead of print]
    Computational methods to explore chromatin state dynamics.
    Elias Orouji, Ayush T Raman.
      The human genome is marked by several singular and combinatorial histone modifications that shape the different states of chromatin and its three-dimensional organization. Genome-wide mapping of these marks as well as histone variants and open chromatin regions is commonly carried out via profiling DNA-protein binding or via chromatin accessibility methods. After the generation of epigenomic datasets in a cell type, statistical models can be used to annotate the noncoding regions of DNA and infer the combinatorial histone marks or chromatin states (CS). These methods involve partitioning the genome and labeling individual segments based on their CS patterns. Chromatin labels enable the systematic discovery of genomic function and activity and can label the gene body, promoters or enhancers without using other genomic maps. CSs are dynamic and change under different cell conditions, such as in normal, preneoplastic or tumor cells. This review aims to explore the available computational tools that have been developed to capture CS alterations under two or more cellular conditions.
    Keywords:  chromatin; chromatin state; epigenomics; histone modification
    DOI:  https://doi.org/10.1093/bib/bbac439
  3. J Biochem. 2022 Oct 07. pii: mvac081. [Epub ahead of print]
    Characterization of KDM5 lysine demethylase family substrate preference and identification of novel substrates.
    Matthew Hoekstra, Nashira H Ridgeway, Kyle K Biggar.
      The KDM5/JARID1 sub-family are 2-oxoglutarate and Fe(II)-dependent lysine-specific histone demethylases that are characterized by their Jumonji catalytic domains. The KDM5 family is known to remove tri-/di-methyl modifications from lysine-4 of histone H3 (i.e., H3-K4me2/3), a mark associated with active gene expression. As a result, studies to date have revolved around the influence of KDM5 on disease through their ability to regulate H3-K4me2/3. Recent evidence demonstrates that KDM5 may influence disease beyond H3-K4 demethylation, making it critical to further investigate KDM5-mediated demethylation of non-histone proteins. To help identify potential non-histone substrates for the KDM5 family, we developed a library of 180 permutated peptide substrates (PPS), with sequences that are systematically altered from the wild-type H3-K4me3 substrate. From this library, we characterized recombinant KDM5A/B/C/D substrate preference and developed recognition motifs for each KDM5 demethylase. The recognition motifs developed were used to predict potential substrates for KDM5A/B/C/D and profiled to generate a list of high-ranking and medium/low-ranking substrates for further in vitro validation. Through this approach, we identified 66 high-ranking substrates in which KDM5 demethylases displayed significant in vitro activity towards.
    Keywords:  Jumonji domain; Lysine demethylase; Non-histone substrates; Permutated substrates; Substrate preference
    DOI:  https://doi.org/10.1093/jb/mvac081
  4. PLoS Comput Biol. 2022 Oct 03. 18(10): e1010576
    Variant calling enhances the identification of cancer cells in single-cell RNA sequencing data.
    William Gasper, Francesca Rossi, Matteo Ligorio, Dario Ghersi.
      Single-cell RNA-sequencing is an invaluable research tool that allows for the investigation of gene expression in heterogeneous cancer cell populations in ways that bulk RNA-seq cannot. However, normal (i.e., non tumor) cells in cancer samples have the potential to confound the downstream analysis of single-cell RNA-seq data. Existing methods for identifying cancer and normal cells include copy number variation inference, marker-gene expression analysis, and expression-based clustering. This work aims to extend the existing approaches for identifying cancer cells in single-cell RNA-seq samples by incorporating variant calling and the identification of putative driver alterations. We found that putative driver alterations can be detected in single-cell RNA-seq data obtained with full-length transcript technologies and noticed that a subset of cells in tumor samples are enriched for putative driver alterations as compared to normal cells. Furthermore, we show that the number of putative driver alterations and inferred copy number variation are not correlated in all samples. Taken together, our findings suggest that augmenting existing cancer-cell filtering methods with variant calling and analysis can increase the number of tumor cells that can be confidently included in downstream analyses of single-cell full-length transcript RNA-seq datasets.
    DOI:  https://doi.org/10.1371/journal.pcbi.1010576
  5. PLoS Genet. 2022 Oct 07. 18(10): e1010451
    Nuclear position modulates long-range chromatin interactions.
    Elizabeth H Finn, Tom Misteli.
      The human genome is non-randomly organized within the cell nucleus. Spatial mapping of genome folding by biochemical methods and imaging has revealed extensive variation in locus interaction frequencies between cells in a population and between homologs within an individual cell. Commonly used mapping approaches typically examine either the relative position of genomic sites to each other or the position of individual loci relative to nuclear landmarks. Whether the frequency of specific chromatin-chromatin interactions is affected by where in the nuclear space a locus is located is unknown. Here, we have simultaneously mapped at the single cell level the interaction frequencies and radial position of more than a hundred locus pairs using high-throughput imaging to ask whether the location within the nucleus affects interaction frequency. We find strong enrichment of many interactions at specific radial positions. Position-dependency of interactions was cell-type specific, correlated with local chromatin type, and cell-type-specific enriched associations were marked by increased variability, sometimes without a significant decrease in mean spatial distance. These observations demonstrate that the folding of the chromatin fiber, which brings genomically distant loci into proximity, and the position of that chromatin fiber relative to nuclear landmarks, are closely linked.
    DOI:  https://doi.org/10.1371/journal.pgen.1010451
  6. Comput Struct Biotechnol J. 2022 ;20 5028-5039
    The synergistic interaction landscape of chromatin regulators reveals their epigenetic regulation mechanisms across five cancer cell lines.
    Meng Cao, Liqiang Wang, Dahua Xu, Xiaoman Bi, Shengnan Guo, Zhizhou Xu, Liyang Chen, Dehua Zheng, Peihu Li, Jiankai Xu, Shaojiang Zheng, Hong Wang, Bo Wang, Jianping Lu, Kongning Li.
      Chromatin regulators (CRs) regulate the gene transcription process through combinatorial patterns, which currently remain obscure for pan-cancer. This study identified the interaction of CRs and constructed CR-CR interaction networks across five tumor cell lines. The global interaction analysis revealed that CRs tend to function in synergistically. In addition, common and specific CRs in interaction networks were identified, and the epigenetic processes of these CRs in regulating gene transcription were analyzed. Common CRs have conserved binding sites but cooperate with different partners in multiple tumor cell lines. They also participate in gene transcription regulation, through mediation of different histone modifications (HMs). Specific CRs, ATF2 and PRDM10 were found to distinguish liver cancer samples with different prognosis. PRDM10 participates in gene transcription regulation, by exertion of influence on the DNA methylation level of liver cancer. Through analysis of the edges in the CR-CR interaction networks, it was found EP300-TAF1 has genome-wide distinct signaling patterns, which exhibit different effects on downstream targets. This analysis provides novel insights for the understanding of synergistic mechanism of CRs function, as controllers of gene transcription across cancer types.
    Keywords:  Chromatin regulators; Combinatorial pattern; Pan-cancer; Transcriptional regulation
    DOI:  https://doi.org/10.1016/j.csbj.2022.09.008
  7. Exp Mol Med. 2022 Oct 07.
    DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities.
    Yasser Abuetabh, H Helena Wu, Chengsen Chai, Habib Al Yousef, Sujata Persad, Consolato M Sergi, Roger Leng.
      Antitumor therapeutic strategies that fundamentally rely on the induction of DNA damage to eradicate and inhibit the growth of cancer cells are integral approaches to cancer therapy. Although DNA-damaging therapies advance the battle with cancer, resistance, and recurrence following treatment are common. Thus, searching for vulnerabilities that facilitate the action of DNA-damaging agents by sensitizing cancer cells is an active research area. Therefore, it is crucial to decipher the detailed molecular events involved in DNA damage responses (DDRs) to DNA-damaging agents in cancer. The tumor suppressor p53 is active at the hub of the DDR. Researchers have identified an increasing number of genes regulated by p53 transcriptional functions that have been shown to be critical direct or indirect mediators of cell fate, cell cycle regulation, and DNA repair. Posttranslational modifications (PTMs) primarily orchestrate and direct the activity of p53 in response to DNA damage. Many molecules mediating PTMs on p53 have been identified. The anticancer potential realized by targeting these molecules has been shown through experiments and clinical trials to sensitize cancer cells to DNA-damaging agents. This review briefly acknowledges the complexity of DDR pathways/networks. We specifically focus on p53 regulators, protein kinases, and E3/E4 ubiquitin ligases and their anticancer potential.
    DOI:  https://doi.org/10.1038/s12276-022-00863-4
  8. Front Cell Dev Biol. 2022 ;10 814722
    The hypoxia-related signature predicts prognosis, pyroptosis and drug sensitivity of osteosarcoma.
    Lin Hu, Xin Wu, Dongjie Chen, Zhenyu Cao, Zian Li, Yanmin Liu, Qiangqiang Zhao.
      Osteosarcoma (OS) is one of the most common types of solid sarcoma with a poor prognosis. Solid tumors are often exposed to hypoxic conditions, while hypoxia is regarded as a driving force in tumor recurrence, metastasis, progression, low chemosensitivity and poor prognosis. Pytoptosis is a gasdermin-mediated inflammatory cell death that plays an essential role in host defense against tumorigenesis. However, few studies have reported relationships among hypoxia, pyroptosis, tumor immune microenvironment, chemosensitivity, and prognosis in OS. In this study, gene and clinical data from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases were merged to develop a hypoxia risk model comprising four genes (PDK1, LOX, DCN, and HMOX1). The high hypoxia risk group had a poor prognosis and immunosuppressive status. Meanwhile, the infiltration of CD8+ T cells, activated memory CD4+ T cells, and related chemokines and genes were associated with clinical survival outcomes or chemosensitivity, the possible crucial driving forces of the OS hypoxia immune microenvironment that affect the development of pyroptosis. We established a pyroptosis risk model based on 14 pyroptosis-related genes to independently predict not only the prognosis but also the chemotherapy sensitivities. By exploring the various connections between the hypoxic immune microenvironment and pyroptosis, this study indicates that hypoxia could influence tumor immune microenvironment (TIM) remodeling and promote pyroptosis leading to poor prognosis and low chemosensitivity.
    Keywords:  drug resistance; hypoxia; osteosarcoma; prognosis; pyroptosis
    DOI:  https://doi.org/10.3389/fcell.2022.814722
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