bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022–04–03
thirteen papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. The Zinc-Dependent HDACs: Non-Histone Substrates and Catalytic Deacylation Beyond Deacetylation.
  2. A single-cell analysis of breast cancer cell lines to study tumour heterogeneity and drug response.
  3. H3K27me3 Demethylase UTX Restrains Plasma Cell Formation.
  4. Phosphorylation-Dependent Regulation of WNT/Beta-Catenin Signaling.
  5. BMI1 promotes osteosarcoma proliferation and metastasis by repressing the transcription of SIK1.
  6. Physiological and pathological roles of the Hippo-YAP/TAZ signaling pathway in liver formation, homeostasis and tumorigenesis.
  7. microRNA-150 targets major epigenetic repressors and inhibits cell proliferation.
  8. Role and regulation of autophagy in cancer.
  9. Comprehensive Analysis of the Differential Expression and Prognostic Value of Histone Deacetylases in Glioma.
  10. Deciphering Molecular Mechanism of Histone Assembly by DNA Curtain Technique.
  11. Collateral responses to classical cytotoxic chemotherapies are heterogeneous and sensitivities are sparse.
  12. Role of the Epigenetic Modifier JMJD6 in Tumor Development and Regulation of Immune Response.
  13. Improvement of resistance to oxaliplatin by vorinostat in human colorectal cancer cells through inhibition of Nrf2 nuclear translocation.
  1. Mini Rev Med Chem. 2022 Mar 30.
    The Zinc-Dependent HDACs: Non-Histone Substrates and Catalytic Deacylation Beyond Deacetylation.
    Weiping Zheng.
      Protein lysine side chain Nε-acylation and -deacylation play an important regulatory role in both epigenetic and non-epigenetic processes via a structural and functional regulation of histone and non-histone proteins. The enzymes catalyzing deacylation were traditionally termed as the histone deacetylases (HDACs) since histone proteins were the first substrates identified and the deacetylation was the first type of deacylation identified. However, it has now been known that, besides the seven sirtuins (i.e. SIRT1-7, theβ-nicotinamide adenine dinucleotide (β-NAD+)-dependent class III HDACs), several of the other eleven members of the mammalian HDAC family (i.e. HDAC1-11, the zinc-dependent classes I, II, and IV HDACs) have been found to also accept non-histone proteins as native substrates and to also catalyze the removal of the acyl groups other than acetyl, such as formyl, crotonyl, and myristoyl. In this mini-review, I will first integrate the current literature coverage on the non-histone substrates and the catalytic deacylation (beyond deacetylation) of the zinc-dependent HDACs, which will be followed by an address on the functional interrogation and pharmacological exploitation (inhibitor design) of the zinc-dependent HDAC-catalyzed deacylation (beyond deacetylation).
    Keywords:  Histone; deacetylation; deacylation; inhibitor.; non-histone; sirtuin; zinc-dependent HDAC
    DOI:  https://doi.org/10.2174/1389557522666220330144151
  2. Nat Commun. 2022 Mar 31. 13(1): 1714
    A single-cell analysis of breast cancer cell lines to study tumour heterogeneity and drug response.
    G Gambardella, G Viscido, B Tumaini, A Isacchi, R Bosotti, D di Bernardo.
      Cancer cells within a tumour have heterogeneous phenotypes and exhibit dynamic plasticity. How to evaluate such heterogeneity and its impact on outcome and drug response is still unclear. Here, we transcriptionally profile 35,276 individual cells from 32 breast cancer cell lines to yield a single cell atlas. We find high degree of heterogeneity in the expression of biomarkers. We then train a deconvolution algorithm on the atlas to determine cell line composition from bulk gene expression profiles of tumour biopsies, thus enabling cell line-based patient stratification. Finally, we link results from large-scale in vitro drug screening in cell lines to the single cell data to computationally predict drug responses starting from single-cell profiles. We find that transcriptional heterogeneity enables cells with differential drug sensitivity to co-exist in the same population. Our work provides a framework to determine tumour heterogeneity in terms of cell line composition and drug response.
    DOI:  https://doi.org/10.1038/s41467-022-29358-6
  3. J Immunol. 2022 Mar 28. pii: ji2100948. [Epub ahead of print]
    H3K27me3 Demethylase UTX Restrains Plasma Cell Formation.
    Anna K Kania, Madeline J Price, Lou-Ella George-Alexander, Dillon G Patterson, Sakeenah L Hicks, Christopher D Scharer, Jeremy M Boss.
      B cell differentiation is associated with substantial transcriptional, metabolic, and epigenetic remodeling, including redistribution of histone 3 lysine 27 trimethylation (H3K27me3), which is associated with a repressive chromatin state and gene silencing. Although the role of the methyltransferase EZH2 (Enhancer of zeste homolog 2) in B cell fate decisions has been well established, it is not known whether H3K27me3 demethylation is equally important. In this study, we showed that simultaneous genetic deletion of the two H3K27 demethylases UTX and JMJD3 (double-knockout [Utx fl/fl Jmjd3 fl/fl Cd19 cre/+] [dKO]) led to a significant increase in plasma cell (PC) formation after stimulation with the T cell-independent Ags LPS and NP-Ficoll. This phenotype occurred in a UTX-dependent manner as UTX single-knockout mice, but not JMJD3 single-knockout mice, mimicked the dKO. Although UTX- and JMJD3-deficient marginal zone B cells showed increased proliferation, dKO follicular B cells also showed increased PC formation. PCs from dKO mice upregulated genes associated with oxidative phosphorylation and exhibited increased spare respiratory capacity. Mechanistically, deletion of Utx and Jmjd3 resulted in higher levels of H3K27me3 at proapoptotic genes and resulted in reduced apoptosis of dKO PCs in vivo. Furthermore, UTX regulated chromatin accessibility at regions containing ETS and IFN regulatory factor (IRF) transcription factor family motifs, including motifs of known repressors of PC fate. Taken together, these data demonstrate that the H3K27me3 demethylases restrain B cell differentiation.
    DOI:  https://doi.org/10.4049/jimmunol.2100948
  4. Front Oncol. 2022 ;12 858782
    Phosphorylation-Dependent Regulation of WNT/Beta-Catenin Signaling.
    Kinjal Shah, Julhash U Kazi.
      WNT/β-catenin signaling is a highly complex pathway that plays diverse roles in various cellular processes. While WNT ligands usually signal through their dedicated Frizzled receptors, the decision to signal in a β-catenin-dependent or -independent manner rests upon the type of co-receptors used. Canonical WNT signaling is β-catenin-dependent, whereas non-canonical WNT signaling is β-catenin-independent according to the classical definition. This still holds true, albeit with some added complexity, as both the pathways seem to cross-talk with intertwined networks that involve the use of different ligands, receptors, and co-receptors. β-catenin can be directly phosphorylated by various kinases governing its participation in either canonical or non-canonical pathways. Moreover, the co-activators that associate with β-catenin determine the output of the pathway in terms of induction of genes promoting proliferation or differentiation. In this review, we provide an overview of how protein phosphorylation controls WNT/β-catenin signaling, particularly in human cancer.
    Keywords:  AXIN; CK1; CTNNB1; GSK3β; adherens junctions; frizzled; β-catenin
    DOI:  https://doi.org/10.3389/fonc.2022.858782
  5. Cancer Cell Int. 2022 Mar 27. 22(1): 136
    BMI1 promotes osteosarcoma proliferation and metastasis by repressing the transcription of SIK1.
    Qiang Wang, Yinghui Wu, Meng Lin, Gaigai Wang, Jinyan Liu, Min Xie, Bo Zheng, Cong Shen, Jun Shen.
       BACKGROUND: Osteosarcoma (OS) is the most common malignant tumor of bone, and the clinical efficacy of current treatments and associated survival rates need to be further improved by employing novel therapeutic strategies. Although various studies have shown that BMI1 protein is universally upregulated in OS cells and tissues, its specific role and underlying mechanism have not yet been fully explored.
    METHODS: Expression of BMI1 protein in OS cells was detected by western blot. The effect of BMI1 on proliferation and migration of OS cells (143B and U-2OS cell lines) was investigated in vitro using CCK-8, colony formation and transwell assays, and in vivo using subcutaneous tumorigenesis and lung metastasis assays in xenograft nude mice. Expression of epithelial-mesenchymal transition (EMT)-associated proteins was detected by immunofluorescence imaging. Bioinformatic analysis was performed using ENCODE databases to predict downstream targets of BMI1. SIK1 mRNA expression in osteosarcoma cells was detected by quantitative real-time reverse transcription PCR (qPCR). Chromatin immunoprecipitation-qPCR (ChIP-qPCR) was used to investigate expression of BMI1-associated, RING1B-associated, H2AK119ub-associated and H3K4me3-associated DNA at the putative binding region of BMI1 on the SIK1 promoter in OS cells.
    RESULTS: Using both in vitro and in vivo experimental approaches, we found that BMI1 promotes OS cell proliferation and metastasis. The tumor suppressor SIK1 was identified as the direct target gene of BMI1 in OS cells. In vitro experiments demonstrated that SIK1 could inhibit proliferation and migration of OS cells. Inhibition of SIK1 largely rescued the altered phenotypes of BMI1-deficient OS cells. Mechanistically, we demonstrated that BMI1 directly binds to the promoter region of SIK1 in a complex with RING1B to promote monoubiquitination of histone H2A at lysine 119 (H2AK119ub) and inhibit H3K4 trimethylation (H3K4me3), resulting in inhibition of SIK1 transcription. We therefore suggest that BMI1 promotes OS cell proliferation and metastasis by inhibiting SIK1.
    CONCLUSIONS: Our results reveal a novel molecular mechanism of OS development promoted by BMI1 and provides a new potential target for OS treatment.
    Keywords:  BMI1; Histone modification; Metastasis; Osteosarcoma(OS); Proliferation; SIK1
    DOI:  https://doi.org/10.1186/s12935-022-02552-8
  6. Cancer Sci. 2022 Mar 29.
    Physiological and pathological roles of the Hippo-YAP/TAZ signaling pathway in liver formation, homeostasis and tumorigenesis.
    Hiroshi Nishina.
      The liver plays central homeostatic roles in metabolism and detoxification, and has a remarkable capacity to fully recover from injuries caused by the various insults to which it is constantly exposed. To fulfill these functions, the liver must maintain a specific size and so must regulate its cell numbers. It must also remove senescent, transformed, and/or injured cells that impair liver function and can lead to diseases such as cirrhosis and liver cancer. Despite their importance, however, the mechanisms governing liver size control and homeostasis have resisted delineation. The discovery of the Hippo intracellular signaling pathway and its downstream effectors, the transcriptional co-activators YAP and TAZ (YAP/TAZ), has provided partial elucidation of these mechanisms. The Hippo-YAP/TAZ pathway is considered to be a cell's sensor of its immediate microenvironment and the cells that surround it, in that this pathway responds to changes in elements such as the extracellular matrix, cell-cell tension, and cell adhesion. Once triggered, Hippo signaling negatively regulates the binding of YAP/TAZ to transcription factors such as TEAD and Smad, controlling their ability to drive gene expression needed for cellular responses such as proliferation, survival, and stemness. Numerous knockout mouse strains lacking YAP/TAZ, as well as transgenic mice showing YAP/TAZ hyperactivation, have been generated, and the effects of these mutations on liver development, size, regeneration, homeostasis and tumorigenesis have been reported. In this review, I summarize the components and regulation of Hippo-YAP/TAZ signaling, and discuss this pathway in the context of liver physiology and pathology.
    Keywords:  Hippo pathway; YAP/TAZ; homeostasis; liver cancer; liver size; regeneration
    DOI:  https://doi.org/10.1111/cas.15352
  7. Exp Cell Res. 2022 Mar 26. pii: S0014-4827(22)00103-3. [Epub ahead of print]415(1): 113110
    microRNA-150 targets major epigenetic repressors and inhibits cell proliferation.
    Murugan Selvam, Venkateshwarlu Bandi, Saravanaraman Ponne, Cheemala Ashok, Sudhakar Baluchamy.
      The Polycomb Repressive Complex (PRC) proteins, EZH2 and EZH1 regulate many biological processes by generating the repressive H3K27me3 modifications in the chromatin. However, the factors that regulate the EZH1/EZH2 functions are poorly studied. We identify that the 3'UTRs of EZH2 and EZH1 mRNAs contain the binding sites for the miRNA, miR-150. MicroRNA-150 (miR-150) controls numerous biological processes including cell proliferation, differentiation and pathogenesis of a variety of diseases including cancer. We find that miR-150 regulates the levels of EZH1 and EZH2 through various experimental investigations. Since EZH2 is known to form a repressive complex with other epigenetic repressors especially DNMT3A and DNMT3B, we investigated whether miR-150 also regulates the DNMT3A and DNMT3B levels. We report that miR-150 regulates DNMT3A and DNMT3B levels through direct and indirect mechanisms respectively. Since these epigenetic repressors promote cell proliferation, we investigated the effect of miR-150 perturbation on HEK293 cell proliferation. We found that miR-150 inhibits cell proliferation and induces S-phase arrest by increasing the levels of tumor suppressors and decreasing the cell cycle regulators. Collectively, our study shows that miR-150 act as a tumor suppressor by down-regulating the oncogenic major epigenetic repressors and controls cell proliferation.
    Keywords:  DNMT3A; DNMT3B; EZH1; EZH2; Epigenetic repressors; miR-150
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113110
  8. Biochim Biophys Acta Mol Basis Dis. 2022 Mar 25. pii: S0925-4439(22)00070-9. [Epub ahead of print]1868(7): 166400
    Role and regulation of autophagy in cancer.
    Ravichandran Rakesh, Loganathan Chandramani PriyaDharshini, Kunnathur Murugesan Sakthivel, Rajan Radha Rasmi.
      Autophagy is an intracellular self-degradative mechanism which responds to cellular conditions like stress or starvation and plays a key role in regulating cell metabolism, energy homeostasis, starvation adaptation, development and cell death. Numerous studies have stipulated the participation of autophagy in cancer, but the role of autophagy either as tumor suppressor or tumor promoter is not clearly understood. However, mechanisms by which autophagy promotes cancer involves a diverse range of modifications of autophagy associated proteins such as ATGs, Beclin-1, mTOR, p53, KRAS etc. and autophagy pathways like mTOR, PI3K, MAPK, EGFR, HIF and NFκB. Furthermore, several researches have highlighted a context-dependent, cell type and stage-dependent regulation of autophagy in cancer. Alongside this, the interaction between tumor cells and their microenvironment including hypoxia has a great potential in modulating autophagy response in favour to substantiate cancer cell metabolism, self-proliferation and metastasis. In this review article, we highlight the mechanism of autophagy and their contribution to cancer cell proliferation and development. In addition, we discuss about tumor microenvironment interaction and their consequence on selective autophagy pathways and the involvement of autophagy in various tumor types and their therapeutic interventions concentrated on exploiting autophagy as a potential target to improve cancer therapy.
    Keywords:  Autophagy; Cancer; Homeostasis; Hypoxia
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166400
  9. Front Cell Dev Biol. 2022 ;10 840759
    Comprehensive Analysis of the Differential Expression and Prognostic Value of Histone Deacetylases in Glioma.
    Jinwei Li, Xianlei Yan, Cong Liang, Hongmou Chen, Meimei Liu, Zhikang Wu, Jiemin Zheng, Junsun Dang, Xiaojin La, Quan Liu.
      Gliomas are the most common and aggressive malignancies of the central nervous system. Histone deacetylases (HDACs) are important targets in cancer treatment. They regulate complex cellular mechanisms that influence tumor biology and immunogenicity. However, little is known about the function of HDACs in glioma. The Oncomine, Human Protein Atlas, Gene Expression Profiling Interactive Analysis, Broad Institute Cancer Cell Line Encyclopedia, Chinese Glioma Genome Atlas, OmicShare, cBioPortal, GeneMANIA, STRING, and TIMER databases were utilized to analyze the differential expression, prognostic value, and genetic alteration of HDAC and immune cell infiltration in patients with glioma. HDAC1/2 were considerable upregulated whereas HDAC11 was significantly downregulated in cancer tissues. HDAC1/2/3/4/5/7/8/11 were significantly correlated with the clinical glioma stage. HDAC1/2/3/10 were strongly upregulated in 11 glioma cell lines. High HDCA1/3/7 and low HDAC4/5/11 mRNA levels were significantly associated with overall survival and disease-free survival in glioma. HDAC1/2/3/4/5/7/9/10/11 are potential useful biomarkers for predicting the survival of patients with glioma. The functions of HDACs and 50 neighboring genes were primarily related to transcriptional dysregulation in cancers and the Notch, cGMP-PKG, and thyroid hormone signaling pathways. HDAC expression was significantly correlated with the infiltration of B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells in glioma. Our study indicated that HDACs are putative precision therapy targets and prognostic biomarkers of survival in glioma patients.
    Keywords:  CGGA, Chinese Glioma Genome Atlas; HDACs; bioinformatics analysis; biomarker; glioma; immune infiltration
    DOI:  https://doi.org/10.3389/fcell.2022.840759
  10. J Vis Exp. 2022 Mar 09.
    Deciphering Molecular Mechanism of Histone Assembly by DNA Curtain Technique.
    Yujin Kang, Subin Bae, Soyeong An, Ja Yil Lee.
      Chromatin is a higher-order structure that packages eukaryotic DNA. Chromatin undergoes dynamic alterations according to the cell cycle phase and in response to environmental stimuli. These changes are essential for genomic integrity, epigenetic regulation, and DNA metabolic reactions such as replication, transcription, and repair. Chromatin assembly is crucial for chromatin dynamics and is catalyzed by histone chaperones. Despite extensive studies, the mechanisms by which histone chaperones enable chromatin assembly remains elusive. Moreover, the global features of nucleosomes organized by histone chaperones are poorly understood. To address these problems, this work describes a unique single-molecule imaging technique named DNA curtain, which facilitates the investigation of the molecular details of nucleosome assembly by histone chaperones. DNA curtain is a hybrid technique that combines lipid fluidity, microfluidics, and total internal reflection fluorescence microscopy (TIRFM) to provide a universal platform for real-time imaging of diverse protein-DNA interactions.Using DNA curtain, the histone chaperone function of Abo1, the Schizosaccharomyces pombe bromodomain-containing AAA+ ATPase, is investigated, and the molecular mechanism underlying histone assembly of Abo1 is revealed. DNA curtain provides a unique approach for studying chromatin dynamics.
    DOI:  https://doi.org/10.3791/63501
  11. Sci Rep. 2022 Mar 31. 12(1): 5453
    Collateral responses to classical cytotoxic chemotherapies are heterogeneous and sensitivities are sparse.
    Simona Dalin, Beatrice Grauman-Boss, Douglas A Lauffenburger, Michael T Hemann.
      Chemotherapy resistance is a major obstacle to curing cancer patients. Combination drug regimens have shown promise as a method to overcome resistance; however, to date only some cancers have been cured with this method. Collateral sensitivity-the phenomenon whereby resistance to one drug is co-occurrent with sensitivity to a second drug-has been gaining traction as a promising new concept to guide rational design of combination regimens. Here we evolved over 100 subclones of the Eµ-Myc; p19ARF-/- cell line to be resistant to one of four classical chemotherapy agents: doxorubicin, vincristine, paclitaxel, and cisplatin. We then surveyed collateral responses to acquisition of resistance to these agents. Although numerous collateral sensitivities have been documented for antibiotics and targeted cancer therapies, we observed only one collateral sensitivity: half of cell lines that acquired resistance to paclitaxel also acquired a collateral sensitivity to verapamil. However, we found that the mechanism of this collateral sensitivity was unrelated to the mechanism of paclitaxel resistance. Interestingly, we observed heterogeneity in the phenotypic response to acquisition of resistance to most of the drugs we tested, most notably for paclitaxel, suggesting the existence of multiple different states of resistance. Surprisingly, this phenotypic heterogeneity in paclitaxel resistant cell lines was unrelated to transcriptomic heterogeneity among those cell lines. These features of phenotypic and transcriptomic heterogeneity must be taken into account in future studies of treated tumor subclones and in design of chemotherapy combinations.
    DOI:  https://doi.org/10.1038/s41598-022-09319-1
  12. Front Immunol. 2022 ;13 859893
    Role of the Epigenetic Modifier JMJD6 in Tumor Development and Regulation of Immune Response.
    Kai Wang, Chao Yang, Haibin Li, Xiaoyan Liu, Meiling Zheng, Zixue Xuan, Zhiqiang Mei, Haiyong Wang.
      JMJD6 is a member of the Jumonji (JMJC) domain family of histone demethylases that contributes to catalyzing the demethylation of H3R2me2 and/or H4R3me2 and regulating the expression of specific genes. JMJD6-mediated demethylation modifications are involved in the regulation of transcription, chromatin structure, epigenetics, and genome integrity. The abnormal expression of JMJD6 is associated with the occurrence and development of a variety of tumors, including breast carcinoma, lung carcinoma, colon carcinoma, glioma, prostate carcinoma, melanoma, liver carcinoma, etc. Besides, JMJD6 regulates the innate immune response and affects many biological functions, as well as may play key roles in the regulation of immune response in tumors. Given the importance of epigenetic function in tumors, targeting JMJD6 gene by modulating the role of immune components in tumorigenesis and its development will contribute to the development of a promising strategy for cancer therapy. In this article, we introduce the structure and biological activities of JMJD6, followed by summarizing its roles in tumorigenesis and tumor development. Importantly, we highlight the potential functions of JMJD6 in the regulation of tumor immune response, as well as the development of JMJD6 targeted small-molecule inhibitors for cancer therapy.
    Keywords:  JMJD6 inhibitor; epigenetic modification; histone demethylation; immune response; tumor immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2022.859893
  13. Biochem Biophys Res Commun. 2022 Mar 23. pii: S0006-291X(22)00401-6. [Epub ahead of print]607 9-14
    Improvement of resistance to oxaliplatin by vorinostat in human colorectal cancer cells through inhibition of Nrf2 nuclear translocation.
    Shota Tanaka, Mika Hosokawa, Ai Tatsumi, Shiho Asaumi, Ryoji Imai, Ken-Ichi Ogawara.
      Vorinostat (suberoylanilide hydroxamic acid: SAHA), a histone deacetylase inhibitor, has potential benefit of improving the resistance to conventional other anti-cancer drugs. This study was aimed to clarify whether SAHA improves the resistance to oxaliplatin (L-OHP), a platinum-based anticancer drug using L-OHP-resistant HCT116 cells (HCT116/OxR), established from colorectal cancer (CRC) cell line HCT116. HCT116/OxR cells showed cross-resistance to other platinum-based drugs. Pre-treatment with SAHA improved the sensitivity of both L-OHP and its metabolite in HCT116/OxR cells, but not in parental HCT116 cells. However, pre-treatment with SAHA did not affect the sensitivity of other platinum-based drugs. These results indicated that SAHA specifically improved the sensitivity of L-OHP in HCT116/OxR cells. Focusing on NF-E2 p45-related factor 2-Kelch-like ECH-associated protein 1 pathway (Nrf2-Keap1) pathway, which is activated by oxidative stress such as the treatment with anti-cancer drugs, mechanisms behind these observations were elucidated. In HCT116/OxR cells transfected with Nrf2 siRNA, the improving effects on L-OHP resistance by SAHA were abolished, suggesting that Nrf2-Keap1 pathway was involved in L-OHP-resistance. In addition, L-OHP metabolite significantly induced the expression of the nuclear protein Nrf2 and its target gene mRNA expression in HCT116/OxR cells. Pre-treatment with SAHA suppressed these changes observed in HCT116/OxR cells. In conclusion, this study demonstrated that SAHA improved L-OHP resistance by inhibiting Nrf2-Keap1 activation via Nrf2 nuclear translocation by L-OHP metabolite.
    Keywords:  Colorectal cancer; Nrf2-Keap1 pathway; Oxaliplatin; Resistance; Vorinostat
    DOI:  https://doi.org/10.1016/j.bbrc.2022.03.070
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