bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒02‒06
ten papers selected by
Ankita Daiya
BITS Pilani
  1. Inhibitors of Jumonji C domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through APC/Cdh1-dependent degradation of CtIP and PAF15.
  2. MYC overexpression leads to increased chromatin interactions at superenhancers and MYC binding sites.
  3. The dCypher Approach to Interrogate Chromatin Reader Activity Against Posttranslational Modification-Defined Histone Peptides and Nucleosomes.
  4. A Liquid State Perspective on Dynamics of Chromatin Compartments.
  5. N6-Methyladenosine-Related LncRNAs Are Potential Remodeling Indicators in the Tumor Microenvironment and Prognostic Markers in Osteosarcoma.
  6. Method to Isolate Dormant Cancer Cells from Heterogeneous Populations.
  7. Super-enhancers modulate interleukin-6 expression and function in cancers.
  8. The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer.
  9. EZH2 Inhibitors: The Unpacking Revolution.
  10. Protein kinase Cα activation switches YAP1 from TEAD-mediated signaling to p73-mediated signaling.
  1. Cancer Biol Ther. 2022 Dec 31. 23(1): 65-75
    Inhibitors of Jumonji C domain-containing histone lysine demethylases overcome cisplatin and paclitaxel resistance in non-small cell lung cancer through APC/Cdh1-dependent degradation of CtIP and PAF15.
    Lei Duan, Ricardo E Perez, Sarah Calhoun, Carl G Maki.
      The Jumonji C domain-containing family of histone lysine demethylases (Jumonji KDMs) have emerged as promising cancer therapy targets. These enzymes remove methyl groups from various histone lysines and, in turn, regulate processes including chromatin compaction, gene transcription, and DNA repair. Small molecule inhibitors of Jumonji KDMs have shown promise in preclinical studies against non-small cell lung cancer (NSCLC) and other cancers. However, how these inhibitors influence cancer therapy responses and/or DNA repair is incompletely understood. In this study, we established cell line and PDX tumor model systems of cisplatin and paclitaxel-resistant NSCLC. We showed that resistant cells and tumors express high levels of Jumonji-KDMs. Knockdown of individual KDMs or treatment with a pan-Jumonji KDM inhibitor sensitized the cells and tumors to cisplatin and paclitaxel and blocked NSCLC in vivo tumor growth. Mechanistically, we found inhibition of Jumonji-KDMs triggers APC/Cdh1-dependent degradation of CtIP and PAF15, two DNA repair proteins that promote repair of cisplatin and paclitaxel-induced DNA lesions. Knockdown of CtIP and PAF15 sensitized resistant cells to cisplatin, indicating their degradation when Jumonji KDMs are inhibited contributes to cisplatin sensitivity. Our results support the idea that Jumonji-KDMs are a targetable barrier to effective therapy responses in NSCLC. Inhibition of Jumonji KDMs increases therapy (cisplatin/paclitaxel) sensitivity in NSCLC cells, at least in part, by promoting APC/Cdh1-dependent degradation of CtIP and PAF15.
    Keywords:  APC/C; CtIP; Histone demethylase; NSCLC; PAF15; cisplatin
    DOI:  https://doi.org/10.1080/15384047.2021.2020060
  2. Genome Res. 2022 Feb 03. pii: gr.276313.121. [Epub ahead of print]
    MYC overexpression leads to increased chromatin interactions at superenhancers and MYC binding sites.
    Yi Xiang See, Kaijing Chen, Melissa J Fullwood.
      The MYC oncogene encodes for the MYC protein and is frequently dysregulated across multiple cancer cell types, making it an attractive target for cancer therapy. MYC overexpression leads to MYC binding at active enhancers, resulting in a global transcriptional amplification of active genes. Since superenhancers are frequently dysregulated in cancer, we hypothesized that MYC preferentially invades into superenhancers and alters the cancer genome organization. To that end, we performed ChIP-seq, RNA-seq, 4C-seq and SIQHiC (Spike-in Quantitative Hi-C) on the U2OS osteosarcoma cell line with tetracycline-inducible MYC MYC overexpression in U2OS cells modulated histone acetylation and increased MYC binding at superenhancers. SIQHiC analysis revealed increased global chromatin contact frequency, particularly at chromatin interactions connecting MYC binding sites at promoters and enhancers. Immunofluorescence staining showed that MYC molecules formed punctate foci at these transcriptionally active domains after MYC overexpression. These results demonstrate the accumulation of overexpressed MYC at promoter-enhancer hubs and suggest that MYC invades into enhancers through spatial proximity. At the same time, the increased protein-protein interactions may strengthen these chromatin interactions to increase chromatin contact frequency. CTCF siRNA knockdown in MYC overexpressed U2OS cells demonstrated that removal of architectural proteins can disperse MYC and abrogate the increase in chromatin contacts. By elucidating the chromatin landscape of MYC driven cancers, we can potentially target MYC associated chromatin interactions for cancer therapy.
    DOI:  https://doi.org/10.1101/gr.276313.121
  3. Methods Mol Biol. 2022 ;2458 231-255
    The dCypher Approach to Interrogate Chromatin Reader Activity Against Posttranslational Modification-Defined Histone Peptides and Nucleosomes.
    Matthew R Marunde, Irina K Popova, Ellen N Weinzapfel, Michael-C Keogh.
      Bulk chromatin encompasses complex sets of histone posttranslational modifications (PTMs) that recruit (or repel) the diverse reader domains of Chromatin-Associated Proteins (CAPs) to regulate genome processes (e.g., gene expression, DNA repair, mitotic transmission). The binding preference of reader domains for their PTMs mediates localization and functional output, and are often dysregulated in disease. As such, understanding chromatin interactions may lead to novel therapeutic strategies, However the immense chemical diversity of histone PTMs, combined with low-throughput, variable, and nonquantitative methods, has defied accurate CAP characterization. This chapter provides a detailed protocol for dCypher, a novel approach for the rapid, quantitative interrogation of CAPs (as mono- or multivalent Queries) against large panels (10s to 100s) of PTM-defined histone peptide and semisynthetic nucleosomes (the potential Targets). We describe key optimization steps and controls to generate robust binding data. Further, we compare the utility of histone peptide and nucleosome substrates in CAP studies, outlining important considerations in experimental design and data interpretation.
    Keywords:  Chromatin binding assay; Histone PTM binding specificity; Histone PTMs; Histone code; Histone peptides; Histone posttranslational modifications; Reader domain; Semisynthetic nucleosomes
    DOI:  https://doi.org/10.1007/978-1-0716-2140-0_13
  4. Front Mol Biosci. 2021 ;8 781981
    A Liquid State Perspective on Dynamics of Chromatin Compartments.
    Rabia Laghmach, Michele Di Pierro, Davit Potoyan.
      The interior of the eukaryotic cell nucleus has a crowded and heterogeneous environment packed with chromatin polymers, regulatory proteins, and RNA molecules. Chromatin polymer, assisted by epigenetic modifications, protein and RNA binders, forms multi-scale compartments which help regulate genes in response to cellular signals. Furthermore, chromatin compartments are dynamic and tend to evolve in size and composition in ways that are not fully understood. The latest super-resolution imaging experiments have revealed a much more dynamic and stochastic nature of chromatin compartments than was appreciated before. An emerging mechanism explaining chromatin compartmentalization dynamics is the phase separation of protein and nucleic acids into membraneless liquid condensates. Consequently, concepts and ideas from soft matter and polymer systems have been rapidly entering the lexicon of cell biology. In this respect, the role of computational models is crucial for establishing a rigorous and quantitative foundation for the new concepts and disentangling the complex interplay of forces that contribute to the emergent patterns of chromatin dynamics and organization. Several multi-scale models have emerged to address various aspects of chromatin dynamics, ranging from equilibrium polymer simulations, hybrid non-equilibrium simulations coupling protein binding and chromatin folding, and mesoscopic field-theoretic models. Here, we review these emerging theoretical paradigms and computational models with a particular focus on chromatin's phase separation and liquid-like properties as a basis for nuclear organization and dynamics.
    Keywords:  chromatin; euchromatin; heterochromatin; imaging; lamin; liquid-liquid phase separation; mesoscale; nuclear organization
    DOI:  https://doi.org/10.3389/fmolb.2021.781981
  5. Front Immunol. 2021 ;12 806189
    N6-Methyladenosine-Related LncRNAs Are Potential Remodeling Indicators in the Tumor Microenvironment and Prognostic Markers in Osteosarcoma.
    Zhongguang Wu, Xiaobo Zhang, Dongjie Chen, Zian Li, Xin Wu, Jianlong Wang, Youwen Deng.
      N6-Adenosine methylation, yielding N6-methyladenosine (m6A), is a reversible epigenetic modification found in messenger RNAs and long non-coding RNAs (lncRNAs), which affects the fate of modified RNA molecules and is essential for the development and differentiation of immune cells in the tumor microenvironment (TME). Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents, and is characterized by high mortality. Currently, the possible role of m6A modifications in the prognosis of OS is unclear. In the present study, we investigated the correlation between m6A-related lncRNA expression and the clinical outcomes of OS patients via a comprehensive analysis. Clinical and workflow-type data were obtained from the Genotype-Tissue Expression Program and The Cancer Genome Atlas. We examined the relationship between m6A modifications and lncRNA expression, conducted Kyoto Encyclopedia of Genes analysis and also gene set enrichment analysis (GSEA), implemented survival analysis to investigate the association of clinical survival data with the expression of m6A-related lncRNAs, and utilized Lasso regression to model the prognosis of OS. Furthermore, we performed immune correlation analysis and TME differential analysis to investigate the infiltration levels of immune cells and their relationship with clinical prognosis. LncRNA expression and m6A levels were closely associated in co-expression analysis. The expression of m6A-related lncRNAs was quite low in tumor tissues; this appeared to be a predicting factor of OS in a prognostic model, independent of other clinical features. The NOD-like receptor signaling pathway was the most significantly enriched pathway in GSEA. In tumor tissues, SPAG4 was overexpressed while ZBTB32 and DEPTOR were downregulated. Tissues in cluster 2 were highly infiltrated by plasma cells. Cluster 2 presented higher ESTIMATE scores and stromal scores, showing a lower tumor cell purity in the TME. In conclusion, m6A-related lncRNA expression is strongly associated with the occurrence and development of OS, and can be used to as a prognostic factor of OS. Moreover, m6A-related lncRNAs and infiltrating immune cells in the TME could serve as new therapeutic targets and prognostic biomarkers for OS.
    Keywords:  N6-methyladenosine (m6A); epigenetic; long non-coding RNAs (lncRNAs); osteosarcoma; plasma cell; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2021.806189
  6. Methods Mol Biol. 2022 ;2394 19-29
    Method to Isolate Dormant Cancer Cells from Heterogeneous Populations.
    Julian A Preciado, Alptekin Aksan.
      Cancer recurrence is responsible for a high percentage of cancer-related deaths. Primary tumor removal, chemotherapy, and radiotherapy often leave behind cancer cells that are clinically undetectable. Recent evidence has shown that subpopulations of these residual cancer cells enter into a prolonged dormant state, remaining quiescent for months to years, and eventually lead to metastases and relapse (Sosa et al. Nat Rev Cancer 14:611-622, 2014). Identifying the presence of and isolating these dormancy-capable cells (DCCs) from resected tumors or bodily fluids may therefore provide an opportunity to understand their biology and develop personalized treatments for patients at risk for relapse. Physical confinement in a stiff and porous 3D matrix, which inhibits proliferation, migration, and growth of the immobilized cells, has been shown to isolate DCC populations (Preciado et al. Technology 05:1-10, 2017; Reátegui et al. J Mater Chem B 2:7440-7448, 2014). Isolated DCCs can then be recovered from the gel and analyzed. Here we describe this immobilization method that can be used to isolate DCCs from heterogeneous cell populations that may also include dormancy-incapable cancer cells and host cells.
    Keywords:  Cancer relapse; Cell immobilization; Dormant cell isolation; Physical confinement; Silica encapsulation; Single cell cancer dormancy
    DOI:  https://doi.org/10.1007/978-1-0716-1811-0_2
  7. Transl Cancer Res. 2020 Sep;9(9): 5555-5565
    Super-enhancers modulate interleukin-6 expression and function in cancers.
    Yuhua Bao, Yingcheng Wu, Baorui Tao, Rong Sun, Ting Lin, Yijian Zheng, Xiaolin Zhu, Haoliang Shen, Weichang Chen, Yihui Fan.
      Background: It is widely accepted that inflammatory cytokine, interleukin 6 (IL-6), was not only elevated in cancer but also important in carcinogenesis. But how did IL-6 be produced in tumor microenvironment remains to be addressed.Methods: Both bioinformatics tools and quantitative real time polymerase chain reaction (RT-PCR) were used to examine the expression of IL-6 in cancer cells. To map super-enhancers of IL-6, sgRNAs were constructed. Stable knockout cells were established and subsequently used for cell proliferation and colony formation assay. The correlation between mapped super-enhancers and IL-6 expression was studied by ATAC-seq analysis.
    Results: The expression of IL-6 was high in multiple cancers, including pancreatic cancer (PAAD). The elevated expression of IL-6 in PAAD was further confirmed by transcriptional data and in a panel of pancreatic cancer cell lines (one immortal HPDE6-C7 cell line and four PDAC cell lines: BxPC-3, PANC-1, AsPC-1 and CFPAC-1). When treated with JQ-1 and I-BET-762, two inhibitors of super-enhancers, the expression of IL-6 in multiple cancer cells including CFPAC-1, HeLa and SUM-159 cells was significantly reduced. By analyzing the H3K27Ac profiling, BRD4 binding, Med1 binding and DNA conservation in CFPAC-1, HeLa and SUM-159 cells, we identified a potential super-enhancer (IL6-SE) that might be important for IL-6 expression in cancer. The super-enhancer (IL6-SE) can be further divided into two elements (IL6-SEa and IL6-SEb). Genetic deletion of IL6-SEa in cancer cells greatly reduces the expression of IL-6. IL6-SEa deficient cells also showed low proliferation and colony formation ability. In patients, the epigenetic activation (ATAC signal) of IL6-SEa is correlated with the expression of IL-6.
    Conclusions: In summary, we not only provide convincing experimental evidence to demonstrate that IL-6 expression in cancer is dependent on super-enhancers but also identified IL6-SEa as a critical DNA regulatory element. Our findings provide new insights to understand the epigenetic regulation of IL-6 expression in cancers.
    Keywords:  BRD4; IL-6; pancreatic cancer; super-enhancers
    DOI:  https://doi.org/10.21037/tcr-19-2825
  8. Clin Sci (Lond). 2022 Feb 11. 136(3): 197-222
    The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer.
    Richard Cunningham, Carsten Gram Hansen.
      Tumorigenesis is a highly complex process, involving many interrelated and cross-acting signalling pathways. One such pathway that has garnered much attention in the field of cancer research over the last decade is the Hippo signalling pathway. Consisting of two antagonistic modules, the pathway plays an integral role in both tumour suppressive and oncogenic processes, generally via regulation of a diverse set of genes involved in a range of biological functions. This review discusses the history of the pathway within the context of cancer and explores some of the most recent discoveries as to how this critical transducer of cellular signalling can influence cancer progression. A special focus is on the various recent efforts to therapeutically target the key effectors of the pathway in both preclinical and clinical settings.
    Keywords:  AlphaFold; Cancer; Hippo pathway; Immuno-oncology; Mesothelioma; Sarcoma
    DOI:  https://doi.org/10.1042/CS20201474
  9. Cancer Res. 2022 Feb 01. 82(3): 359-361
    EZH2 Inhibitors: The Unpacking Revolution.
    Vera Adema, Simona Colla.
      The methylation of lysine 27 on histone H3 (H3K27me3) is a chromatin mark associated with nucleosome condensation and gene expression silencing. EZH2 is a lysine methyltransferase that catalyzes H3K27me3. In this issue of Cancer Research, Porazzi and colleagues report that pretreatment with EZH2 inhibitors opened up the H3K27me3-marked chromatin of acute myeloid leukemia (AML) cells, which enhanced DNA damage and apoptosis induced by chemotherapeutic agents, in particular the topoisomerase II inhibitors, doxorubicin and etoposide. The EZH2 inhibitor/doxorubicin combination also enabled the expression of proapoptotic genes, potentially contributing to the death of AML cells. This study has significant implications for improving the efficacy of DNA-damaging cytotoxic agents in AML, thereby enabling lower chemotherapy doses and reducing treatment-related side effects.See related article by Porazzi et al., p. 458.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-4311
  10. Cancer Sci. 2022 Feb 01.
    Protein kinase Cα activation switches YAP1 from TEAD-mediated signaling to p73-mediated signaling.
    Caleb Kwame Sinclear, Junichi Maruyama, Shunta Nagashima, Kyoko Arimoto-Matsuzaki, Joshua Agbemefa Kuleape, Hiroaki Iwasa, Hiroshi Nishina, Yutaka Hata.
      Yes-associated protein 1 (YAP1) interacts with TEAD transcription factor in the nucleus and up-regulates TEAD-target genes. YAP1 is phosphorylated by large tumor suppressor (LATS) kinases, the core kinases of the Hippo pathway, at five serine residues and is sequestered and degraded in the cytoplasm. In human cancers with the dysfunction of the Hippo pathway, YAP1 becomes hyperactive and confers malignant properties to cancer cells. We have observed that cold shock induces protein kinase C (PKC)-mediated phosphorylation of YAP1. PKC phosphorylates YAP1 at three serine residues among LATS-mediate phosphorylation sites. Importantly, PKC activation recruits YAP1 to the cytoplasm even in LATS-depleted cancer cells and reduces the co-operation with TEAD. PKC activation induces promyelocytic leukemia protein-mediated sumoylation of YAP1. Sumoylated YAP1 remains in the nucleus, binds to p73, and promotes p73-target gene transcription. Bryostatin, a natural anti-neoplastic reagent that activates PKC, induces YAP1/p73-mediated apoptosis in cancer cells. Bryostatin reverses malignant transformation caused by the depletion of LATS kinases. Hence, bryostatin and other reagents that activate PKC are expected to control cancers with the dysfunction of the Hippo pathway.
    Keywords:  Hippo pathway; TEAD; TP73; YAP1; promyelocytic leukemia protein; protein kinase C; sumoylation
    DOI:  https://doi.org/10.1111/cas.15285
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