bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒06‒19
thirteen papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Roles of YAP/TAZ in ferroptosis.
  2. Coming full circle: on the origin and evolution of the looping model for enhancer-promoter communication.
  3. The Hippo pathway drives the cellular response to hydrostatic pressure.
  4. The interplay between noncoding RNA and YAP/TAZ signaling in cancers: molecular functions and mechanisms.
  5. YAP knockdown in combination with ferroptosis induction increases the sensitivity of HOS human osteosarcoma cells to Pyropheophorbide-α methyl ester-mediated photodynamic therapy.
  6. Disorders of histone methylation: molecular basis and clinical syndromes.
  7. Evidence that HDAC7 acts as an epigenetic "reader" of AR acetylation through NCoR-HDAC3 dissociation.
  8. Exosomal CTCF Confers Cisplatin Resistance in Osteosarcoma by Promoting Autophagy via the IGF2-AS/miR-579-3p/MSH6 Axis.
  9. Dynamic Chromatin States Coupling with Key Transcription Factors in Colitis-Associated Colorectal Cancer.
  10. YAP1 maintains active chromatin state in head and neck squamous cell carcinomas that promotes tumorigenesis through cooperation with BRD4.
  11. Nuclear βII-Tubulin and its Possible Utility in Cancer Diagnosis, Prognosis and Treatment.
  12. CBX8 Promotes Cell Proliferation and Metastasis and Leads to Radiotherapy Tolerance of Glioma Cells.
  13. Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment.
  1. Trends Cell Biol. 2022 Jun 11. pii: S0962-8924(22)00136-2. [Epub ahead of print]
    Roles of YAP/TAZ in ferroptosis.
    Suchitra Magesh, Danfeng Cai.
      Ferroptosis is a unique iron-dependent form of regulated cell death. Recently, researchers found that ferroptosis was sensitive to cell density, regulated by Hippo signaling. This article summarizes the roles of the Hippo pathway effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in ferroptosis and the therapeutic potential of activating ferroptosis in cancer.
    Keywords:  Hippo pathway; TAZ; YAP; ferroptosis
    DOI:  https://doi.org/10.1016/j.tcb.2022.05.005
  2. J Biol Chem. 2022 Jun 09. pii: S0021-9258(22)00558-0. [Epub ahead of print] 102117
    Coming full circle: on the origin and evolution of the looping model for enhancer-promoter communication.
    Tessa M Popay, Jesse R Dixon.
      In mammalian organisms, enhancers can regulate transcription from great genomic distances. How enhancers affect distal gene expression has been a major question in the field of gene regulation. One model to explain how enhancers communicate with their target promoters, the chromatin looping model, posits that enhancers and promoters come in close spatial proximity to mediate communication. Chromatin looping has been broadly accepted as a means for enhancer-promoter communication, driven by accumulating in vitro and in vivo evidence. The genome is now known to be folded into a complex 3D arrangement, created and maintained in part by the interplay of the Cohesin complex and the DNA binding protein CTCF. In the last few years, however, doubt over the relationship between looping and transcriptional activation has emerged, driven by studies finding that only a modest number of genes are perturbed with acute degradation of looping machinery components. In parallel, newer models describing distal enhancer action have also come to prominence. In this manuscript, we explore the emergence and development of the looping model as a means for enhancer-promoter communication and review the contrasting evidence between historical gene-specific and current global data for the role of chromatin looping in transcriptional regulation. We also discuss the evidence for alternative models to chromatin looping and their support in the literature. We suggest that, while there is abundant evidence for chromatin looping as a major mechanism for enhancer function, enhancer-promoter communication is likely mediated by more than one mechanism in an enhancer- and context-dependent manner.
    Keywords:  3D genome; CTCF; Cohesin; TAD; chromatin structure; genome structure; promoter; transcription; transcription enhancer
    DOI:  https://doi.org/10.1016/j.jbc.2022.102117
  3. EMBO J. 2022 Jun 15. e108719
    The Hippo pathway drives the cellular response to hydrostatic pressure.
    Jiwon Park, Siyang Jia, Donald Salter, Pierre Bagnaninchi, Carsten G Hansen.
      Cells need to rapidly and precisely react to multiple mechanical and chemical stimuli in order to ensure precise context-dependent responses. This requires dynamic cellular signalling events that ensure homeostasis and plasticity when needed. A less well-understood process is cellular response to elevated interstitial fluid pressure, where the cell senses and responds to changes in extracellular hydrostatic pressure. Here, using quantitative label-free digital holographic imaging, combined with genome editing, biochemical assays and confocal imaging, we analyse the temporal cellular response to hydrostatic pressure. Upon elevated cyclic hydrostatic pressure, the cell responds by rapid, dramatic and reversible changes in cellular volume. We show that YAP and TAZ, the co-transcriptional regulators of the Hippo signalling pathway, control cell volume and that cells without YAP and TAZ have lower plasma membrane tension. We present direct evidence that YAP/TAZ drive the cellular response to hydrostatic pressure, a process that is at least partly mediated via clathrin-dependent endocytosis. Additionally, upon elevated oscillating hydrostatic pressure, YAP/TAZ are activated and induce TEAD-mediated transcription and expression of cellular components involved in dynamic regulation of cell volume and extracellular matrix. This cellular response confers a feedback loop that allows the cell to robustly respond to changes in interstitial fluid pressure.
    Keywords:  YAP/TAZ; cell volume; endocytosis; holographic imaging; membrane tension
    DOI:  https://doi.org/10.15252/embj.2021108719
  4. J Exp Clin Cancer Res. 2022 Jun 14. 41(1): 202
    The interplay between noncoding RNA and YAP/TAZ signaling in cancers: molecular functions and mechanisms.
    Yirao Zhang, Yang Wang, Hao Ji, Jie Ding, Keming Wang.
      The Hippo signaling pathway was found coordinately modulates cell regeneration and organ size. Its dysregulation contributes to uncontrolled cell proliferation and malignant transformation. YAP/TAZ are two critical effectors of the Hippo pathway and have been demonstrated essential for the initiation or growth of most tumors. Noncoding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, have been shown to play critical roles in the development of many cancers. In the past few decades, a growing number of studies have revealed that ncRNAs can directly or indirectly regulate YAP/TAZ signaling. YAP/TAZ also regulate ncRNAs expression in return. This review summarizes the interactions between YAP/TAZ signaling and noncoding RNAs together with their biological functions on cancer progression. We also try to describe the complex feedback loop existing between these components.
    Keywords:  Carcinogenesis; TAZ; YAP; ncRNA
    DOI:  https://doi.org/10.1186/s13046-022-02403-4
  5. Photodiagnosis Photodyn Ther. 2022 Jun 12. pii: S1572-1000(22)00250-2. [Epub ahead of print] 102964
    YAP knockdown in combination with ferroptosis induction increases the sensitivity of HOS human osteosarcoma cells to Pyropheophorbide-α methyl ester-mediated photodynamic therapy.
    Fangbiao Zhan, Ye Zhang, Qiang Zuo, Chaozheng Xie, Huanhuan Li, Ling Tian, Chunrong Wu, Zhiyu Chen, Chaohua Yang, Yang Wang, Qiaochu Li, Tao He, Haoyang Yu, Jian Chen, Jiangxia Xiang, Yunsheng Ou.
      BACKGROUND AND AIMS: This study was designed to explore the effects of Yes-associated protein (YAP) knockdown on human osteosarcoma (HOS) cell sensitivity to Pyropheophorbide-α methyl ester-mediated photodynamic therapy (MPPa-PDT), and to assess how YAP silencing in combination with treatment with the ferroptosis inducer Erastin improves HOS cell sensitivity to MPPa-PDT in an effort to better clarify the molecular mechanisms underlying these phenotypes.METHODS: At 12 h post-MPPa-PDT, Hoechst staining and flow cytometry were conducted to evaluate the apoptotic death of HOS cells. The expression of YAP in these cells at 12 h post-MPPa-PDT treatment was assessed via Western blotting and immunofluorescent staining. BODIPY581/591-C11 was used to evaluate lipid peroxidation. Following shYAP lentiviral transduction, Western blotting was conducted to assess the expression of proteins associated with proliferation, apoptosis, and ferroptosis. EdU assays and clonogenic assays were performed to analyze cellular proliferation. Erastin-treated HOS cells were used to establish a ferroptosis model. Western blotting was used to measure ferroptosis-associated protein levels following shYAP and erastin treatment, while changes in proliferation and MDA levels in each group were examined using an MDA kit.
    RESULTS: At 12 h post-MPPa-PDT, HOS cells exhibited apoptotic characteristics including nuclear fragmentation and pyknosis, with concomitant increases in apoptosis-associated proteins as detected via Western blotting and apoptotic induction as measured via flow cytometry. Phosphorylated YAP levels fell and non-phosphorylated YAP levels rose following such treatment. Transfection with shYAP was successful as a means of generating stable HOS cell lines, and Western blotting analyses of these cells revealed reductions in proteins associated with cellular proliferation together with the upregulation of apoptosis-related proteins.  MDA assays indicated that erastin combined with YAP knockdown enhanced the sensitivity of HOS cells to MPPa-PDT treatment.
    CONCLUSIONS: These data indicate that ferroptosis and YAP knockdown can enhance osteosarcoma cell sensitivity to MPPa-PDT therapy.
    Keywords:  Apoptosis; Ferroptosis; MPPa-PDT; Osteosarcoma; YAP
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.102964
  6. Clin Genet. 2022 Jun 17.
    Disorders of histone methylation: molecular basis and clinical syndromes.
    Mode Al Ojaimi, Bashar J Banimortada, Amna Othman, Korbinian M Riedhammer, Mohammed Almannai, Ayman W El-Hattab.
      Epigenetic modifications of DNA and histone tails are essential for gene expression regulation. They play an essential role in neurodevelopment as nervous system development is a complex process requiring a dynamic pattern of gene expression. Histone methylation is one of the vital epigenetic regulators and mostly occurs on lysine residues of histones H3 and H4. Histone methylation is catalyzed by two sets of enzymes: histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). KMT2 enzymes form a distinct multi-subunit complex known as COMPASS to enhance their catalytic activity and diversify their biologic functions. Several neurodevelopmental syndromes result from defects of histone methylation which can be caused by deficiencies in histone methyltransferases and demethylases, loss of the histone methyltransferase activator TASP1, or derangements in COMPASS formation. In this review article, the molecular mechanism of histone methylation is discussed followed by summarizing clinical syndromes caused by monogenic defects in histone methylation.
    Keywords:  COMPASS; epigenetics; histone demethylases; histone methylation; histone methyltransferases; neurodevelopmental disorders
    DOI:  https://doi.org/10.1111/cge.14181
  7. Cell Chem Biol. 2022 Jun 10. pii: S2451-9456(22)00200-8. [Epub ahead of print]
    Evidence that HDAC7 acts as an epigenetic "reader" of AR acetylation through NCoR-HDAC3 dissociation.
    Yuchen Zhang, Rafael Andrade, Anthony A Hanna, Mary Kay H Pflum.
      Histone deacetylase (HDAC) proteins are epigenetic regulators that govern a wide variety of cellular events. With a role in cancer formation, HDAC inhibitors have emerged as anti-cancer therapeutics. Among the eleven metal-dependent class I, II, and IV HDAC proteins targeted by inhibitor drugs, class IIa HDAC4, -5, -7, and -9 harbor low deacetylase activity and are hypothesized to be "reader" proteins, which bind to post-translationally acetylated lysine. However, evidence linking acetyllysine binding to a downstream functional event is lacking. Here, we report for the first time that HDAC4, -5, and -7 dissociated from corepressor NCoR in the presence of an acetyllysine-containing peptide, consistent with reader function. Documenting the biological consequences of this possible reader function, mutation of a critical acetylation site regulated androgen receptor (AR) transcriptional activation function through HDAC7-NCoR-HDAC3 dissociation. The data document the first evidence consistent with epigenetic-reader functions of class IIa HDAC proteins.
    Keywords:  HDAC7; NCoR; androgen receptor; epigenetic reader; histone deacetylase
    DOI:  https://doi.org/10.1016/j.chembiol.2022.05.008
  8. J Oncol. 2022 ;2022 9390611
    Exosomal CTCF Confers Cisplatin Resistance in Osteosarcoma by Promoting Autophagy via the IGF2-AS/miR-579-3p/MSH6 Axis.
    Haibo Zhan, Jun Xiao, Po Wang, Fengbo Mo, Kaihuang Li, Fengfen Guo, Xiaolong Yu, Xuqiang Liu, Bin Zhang, Min Dai, Hucheng Liu.
      Cancer-derived exosomes participate in carcinogenesis and progression of cancers, including metastasis and drug-resistance. Of note, CTCF has been suggested to induce drug resistance in various cancers. Herein, we aim to investigate the role of cisplatin- (CDDP-) resistant osteosarcoma- (OS-) derived exosomal CTCF in OS cell resistance to CDDP and its mechanistic basis. Differentially expressed transcription factors, long noncoding RNAs (lncRNAs), miRNAs, and genes in OS were retrieved using bioinformatics approaches. Exosomes were extracted from CDDP-resistant OS cells and then cocultured with parental OS cells, followed by lentiviral transduction to manipulate the expression of CTCF, IGF2-AS, miR-579-3p, and MSH6. We assessed the in vitro and in vivo effects on malignant phenotypes, autophagy, CDDP sensitivity, and tumor formation of OS cells. It was established that CTCF and IGF2-AS were highly expressed in CDDP-resistant OS cells, and the CDDP-resistant OS cell-derived exosomal CTCF enhanced IGF2-AS transcription. CDDP-resistant OS-derived exosomes transmitted CTCF to OS cells and increased CDDP resistance in OS cells by activating an autophagy-dependent pathway. Mechanistically, CTCF activated IGF2-AS transcription and IGF2-AS competitively bound to miR-579-3p to upregulate MSH6 expression. Additionally, the promoting function of exosomal CTCF-mediated IGF2-AS/miR-579-3p/MSH6 in OS cell resistance to CDDP was confirmed in vivo. Taken together, CDDP-resistant OS-derived exosomal CTCF enhanced resistance of OS cells to CDDP via activating the autophagy-dependent pathway, providing a potential therapeutic consideration for OS treatment.
    DOI:  https://doi.org/10.1155/2022/9390611
  9. Adv Sci (Weinh). 2022 Jun 16. e2200536
    Dynamic Chromatin States Coupling with Key Transcription Factors in Colitis-Associated Colorectal Cancer.
    Lin Chen, Zhihui Luo, Chen Zhao, Qinglan Li, Yingjie Geng, Yong Xiao, Ming-Kai Chen, Lianyun Li, Zhen-Xia Chen, Min Wu.
      Inflammation is one of the critical risk factors for colorectal cancer (CRC). However, the mechanisms for transition from colitis to CRC remain elusive. Recently, epigenetic changes have emerged as important regulatory factors for colitis-associated cancer. Here, a systematic epigenomic study of histone modifications is performed, including H3K4me1, H3K4me3, H3K27ac, H3K27me3 and H3K9me3, in an AOM-DSS-induced CRC mouse model. In combination with transcriptomic data, the authors generate a dataset of 105 deep sequencing files and illustrate the dynamic landscape of chromatin states at five time points during inflammation-cancer transition. Functional gene clusters are identified based on dynamic transcriptomic and epigenomic information, and key signaling pathways in the process are illustrated. This study's results reveal that enhancer state regions play important roles during inflammation-cancer transition. It predicts novel transcription factors based on enhancer information, and experimentally proves OTX2 as a critical tumor suppressive transcription factor. Taken together, this study provides comprehensive epigenomic data and reveals novel molecular mechanisms for colitis-associated cancer.
    Keywords:  NF-κB, OTX2; chromatin states; colitis-associated cancer; histone modification
    DOI:  https://doi.org/10.1002/advs.202200536
  10. Cell Rep. 2022 Jun 14. pii: S2211-1247(22)00756-2. [Epub ahead of print]39(11): 110970
    YAP1 maintains active chromatin state in head and neck squamous cell carcinomas that promotes tumorigenesis through cooperation with BRD4.
    Nana Chen, Gabriel Golczer, Subhoshree Ghose, Brian Lin, Adam Langenbucher, Jason Webb, Haymanti Bhanot, Nicholas B Abt, Derrick Lin, Mark Varvares, Martin Sattler, Ann Marie Egloff, Richard Joh, Ravindra Uppaluri, Kevin S Emerick, Michael S Lawrence, Srinivas Vinod Saladi.
      Analysis of The Cancer Genome Atlas and other published data of head and neck squamous cell carcinoma (HNSCC) reveals somatic alterations of the Hippo-YAP pathway in approximately 50% of HNSCC. Better strategies to target the YAP1 transcriptional complex are sought. Here, we show that FAT1, an upstream inhibitor of YAP1, is mutated either by missense or by truncating mutation in 29% of HNSCC. Comprehensive proteomic and drug-screening studies across pan-cancer models confirm that FAT1-mutant HNSCC exhibits selective and higher sensitivity to BRD4 inhibition by JQ1. Epigenomic analysis reveals an active chromatin state in FAT1-mutant HNSCC cells that is driven by the YAP/TAZ transcriptional complex through recruitment of BRD4 to deposit active histone marks, thereby maintaining an oncogenic transcriptional state. This study reveals a detailed cooperative mechanism between YAP1 and BRD4 in HNSCC and suggests a specific therapeutic opportunity for the treatment of this subset of head and neck cancer patients.
    Keywords:  ATAD2; BRD4; CP: Cancer; CP: Molecular biology; FAT1 mutation; HNSCC; JQ1; NRG1; OTX-015; PD-L1; YAP1; hippo pathway
    DOI:  https://doi.org/10.1016/j.celrep.2022.110970
  11. Front Cell Dev Biol. 2022 ;10 870088
    Nuclear βII-Tubulin and its Possible Utility in Cancer Diagnosis, Prognosis and Treatment.
    Richard F Ludueña, Consuelo Walss-Bass, Anna Portyanko, Jiayan Guo, I-Tien Yeh.
      Microtubules are organelles that usually occur only in the cytosol. Walss et al. (1999) discovered the βII isotype of tubulin, complexed with α, in the nuclei of certain cultured cells, in non-microtubule form. When fluorescently labeled tubulins were microinjected into the cells, only αβII appeared in the nucleus, and only after one cycle of nuclear disassembly and reassembly. It appeared as if αβII does not cross the nuclear envelope but is trapped in the nucleus by the re-forming nuclear envelope in whose reassembly βII may be involved. βII is present in the cytoplasm and nuclei of many tumor cells. With some exceptions, normal tissues that expressed βII rarely had βII in their nuclei. It is possible that βII is involved in nuclear reassembly and then disappears from the nucleus. Ruksha et al. (2019) observed that patients whose colon cancer cells in the invasive front showed no βII had a median survival of about 5.5 years, which was more than halved if they had cytosolic βII and further lessened if they had nuclear βII, suggesting that the presence and location of βII in biopsies could be a useful prognostic indicator and also that βII may be involved in cancer progression. Yeh and Ludueña. (2004) observed that many tumors were surrounded by non-cancerous cells exhibiting cytosolic and nuclear βII, suggesting a signaling pathway that causes βII to be synthesized in nearby cells and localized to their nuclei. βII could be useful in cancer diagnosis, since the presence of βII in non-cancerous cells could indicate a nearby tumor. Investigation of this pathway might reveal novel targets for chemotherapy. Another possibility would be to combine αβII with CRISPR-Cas9. This complex would likely enter the nucleus of a cancer cell and, if guided to the appropriate gene, might destroy the cancer cell or make it less aggressive; possible targets will be discussed here. The possibilities raised here about the utility of βII in cancer diagnosis, prognosis, biology and therapy may repay further investigation.
    Keywords:  Beta-II-Tubulin; CRISPR-Cas9; Cancer prognosis; cancer diagnosis; cancer treatment; nucleus
    DOI:  https://doi.org/10.3389/fcell.2022.870088
  12. Turk Neurosurg. 2021 Nov 22.
    CBX8 Promotes Cell Proliferation and Metastasis and Leads to Radiotherapy Tolerance of Glioma Cells.
    Qiang Liu, Xianguo Li, Wenhong Gao.
      AIM: Glioma is the most common primary tumor of the brain and spinal cord. Postoperative adjuvant radiotherapy and chemotherapy are conventional treatment methods. Resistance to these methods drives poor prognosis. CBX8, an important part of the polycomb inhibition complex, plays a significant role in various malignant tumors. However, its role has not been clearly reported, especially within DNA damage repair pathways.MATERIAL AND METHODS: Detect CBX8 expression in glioma cells and clinical samples by qPCR and Western blot. Overexpression and knockdown CBX8 cell lines were constructed by lentivirus infection. CCK8, wound healing, and transwell assays were used to verify the effects of CBX8 on proliferation, migration, and invasion of glioma cells. After radiation treatment, CCK8 and colony formation assays were used to detect cell sensitivity of CBX8 expression levels to radiotherapy. Western blot detected expression levels of p-ATM, p-ATR, BRCA-1, RAD51, and P53 in various cells after radiation treatment, demonstrating CBX8's effect on DNA damage and repair proteins. Finally, the sensitivity of tumors with different CBX8 expression levels to radiotherapy was verified in vivo.
    RESULTS: CBX8 expression is significantly increased in glioma. High CBX8 expression promotes proliferation, invasion, and migration of glioma cells. It also causes glioma cells to resist radiotherapy. CBX8 affects protein expression related to DNA damage repair. In vivo, tumors with low CBX8 expression are more sensitive to radiotherapy.
    CONCLUSION: CBX8 promotes proliferation and metastasis of glioma cells and reduces cell sensitivity to radiotherapy by affecting DNA damage repair pathways.
    DOI:  https://doi.org/10.5137/1019-5149.JTN.35022-21.2
  13. Front Cell Dev Biol. 2022 ;10 835273
    Cellular Heterogeneity and Cooperativity in Glioma Persister Cells Under Temozolomide Treatment.
    Marion Rabé, Lucie Fonteneau, Lisa Oliver, Alvaro Morales-Molina, Camille Jubelin, Javier Garcia-Castro, Dominique Heymann, Catherine Gratas, François M Vallette.
      We have observed a drug-tolerant/persister state in a human glioblastoma (GBM) cell line after exposure to temozolomide, the standard-of-care chemotherapeutic agent for GBM. We used a multicolor lentiviral genetic barcode labeling to follow cell population evolution during temozolomide treatment. We observed no change in the distribution of the different colored populations of cells in persister or resistant cells suggesting that pre-existing minor subpopulations, which would be expected to be restricted to a single color, were not amplified/selected during the response to the drug. We have previously identified four genes (CHI3L1, FAT2, KLK5, and HB-EGF) that were over-expressed during the persister stage. Single-cell analysis of these four genes indicated that they were expressed in different individual cells ruling out the existence of a single persister-specific clone but suggesting rather a global answer. Even so, the transitory silencing of CHI3L1, FAT2, or KLK5 influenced the expression of the other three genes and the survival of U251 cells in absence of temozolomide. Since proteins encoded by the four genes are all localized in the extracellular matrix or interact within the extracellular compartment, we propose that cellular interactions and communications are important during the persister stage before the acquisition of chemo-resistance. Thus, persisters might be a new therapeutically relevant target in GBM.
    Keywords:  barcoding; clones; glioma; persisters; resistance
    DOI:  https://doi.org/10.3389/fcell.2022.835273
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