bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒08‒21
thirteen papers selected by
Ankita Daiya
BITS Pilani
  1. Mastering the use of cellular barcoding to explore cancer heterogeneity.
  2. The molecular understanding of super-enhancer dysregulation in cancer.
  3. Transcriptional Heterogeneity of Cellular Senescence in Cancer.
  4. Differential molecular mechanistic behavior of HDACs in cancer progression.
  5. TRANSCRIPTIONAL ANALYSIS OF ZINC-DEPENDENT HISTONE DEACETYLASES IN SEVERAL HUMAN CANCER CELLS.
  6. Mutually exclusive expression of EZH2 and H3K27me3 in non-small cell lung carcinoma.
  7. Chromatin Dynamics in Digestive System Cancer: Commander and Regulator.
  8. Oncohistones: Exposing the nuances and vulnerabilities of epigenetic regulation.
  9. Inferring gene regulation from stochastic transcriptional variation across single cells at steady state.
  10. Mechanical stretch aggravates vascular smooth muscle cell apoptosis and vascular remodeling by downregulating EZH2.
  11. Distinct osteogenic effect of different periosteum derived cells via Hippo-YAP cascade signaling.
  12. Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni.
  13. Pan-cancer gene expression analysis: Identification of deregulated autophagy genes and drugs to target them.
  1. Nat Rev Cancer. 2022 Aug 18.
    Mastering the use of cellular barcoding to explore cancer heterogeneity.
    Antonin Serrano, Jean Berthelet, Shalin H Naik, Delphine Merino.
      Tumours are often composed of a multitude of malignant clones that are genomically unique, and only a few of them may have the ability to escape cancer therapy and grow as symptomatic lesions. As a result, tumours with a large degree of genomic diversity have a higher chance of leading to patient death. However, clonal fate can be driven by non-genomic features. In this context, new technologies are emerging not only to track the spatiotemporal fate of individual cells and their progeny but also to study their molecular features using various omics analysis. In particular, the recent development of cellular barcoding facilitates the labelling of tens to millions of cancer clones and enables the identification of the complex mechanisms associated with clonal fate in different microenvironments and in response to therapy. In this Review, we highlight the recent discoveries made using lentiviral-based cellular barcoding techniques, namely genetic and optical barcoding. We also emphasize the strengths and limitations of each of these technologies and discuss some of the key concepts that must be taken into consideration when one is designing barcoding experiments. Finally, we suggest new directions to further improve the use of these technologies in cancer research.
    DOI:  https://doi.org/10.1038/s41568-022-00500-2
  2. Nagoya J Med Sci. 2022 May;84(2): 216-229
    The molecular understanding of super-enhancer dysregulation in cancer.
    Seiko Yoshino, Hiroshi I Suzuki.
      Abnormalities in the regulation of gene expression are associated with various pathological conditions. Among the distal regulatory elements in the genome, the activation of target genes by enhancers plays a central role in the formation of cell type-specific gene expression patterns. Super-enhancers are a subclass of enhancers that frequently contain multiple enhancer-like elements and are characterized by dense binding of master transcription factors and Mediator complexes and high signals of active histone marks. Super-enhancers have been studied in detail as important regulatory regions that control cell identity and contribute to the pathogenesis of diverse diseases. In cancer, super-enhancers have multifaceted roles by activating various oncogenes and other cancer-related genes and shaping characteristic gene expression patterns in cancer cells. Alterations in super-enhancer activities in cancer involve multiple mechanisms, including the dysregulation of transcription factors and the super-enhancer-associated genomic abnormalities. The study of super-enhancers could contribute to the identification of effective biomarkers and the development of cancer therapeutics targeting transcriptional addiction. In this review, we summarize the roles of super-enhancers in cancer biology, with a particular focus on hematopoietic malignancies, in which multiple super-enhancer alteration mechanisms have been reported.
    Keywords:  cancer therapy; genome; oncogene; super-enhancer; transcription factor
    DOI:  https://doi.org/10.18999/nagjms.84.2.216
  3. Mol Cells. 2022 Aug 19.
    Transcriptional Heterogeneity of Cellular Senescence in Cancer.
    Muhammad Junaid, Aejin Lee, Jaehyung Kim, Tae Jun Park, Su Bin Lim.
      Cellular senescence plays a paradoxical role in tumorigenesis through the expression of diverse senescence-associated (SA) secretory phenotypes (SASPs). The heterogeneity of SA gene expression in cancer cells not only promotes cancer stemness but also protects these cells from chemotherapy. Despite the potential correlation between cancer and SA biomarkers, many transcriptional changes across distinct cell populations remain largely unknown. During the past decade, single-cell RNA sequencing (scRNA-seq) technologies have emerged as powerful experimental and analytical tools to dissect such diverse senescence-derived transcriptional changes. Here, we review the recent sequencing efforts that successfully characterized scRNA-seq data obtained from diverse cancer cells and elucidated the role of senescent cells in tumor malignancy. We further highlight the functional implications of SA genes expressed specifically in cancer and stromal cell populations in the tumor microenvironment. Translational research leveraging scRNA-seq profiling of SA genes will facilitate the identification of novel expression patterns underlying cancer susceptibility, providing new therapeutic opportunities in the era of precision medicine.
    Keywords:  cancer; cellular heterogeneity; senescence; single-cell RNA sequencing
    DOI:  https://doi.org/10.14348/molcells.2022.0036
  4. Med Oncol. 2022 Aug 16. 39(11): 171
    Differential molecular mechanistic behavior of HDACs in cancer progression.
    Tashvinder Singh, Prabhsimran Kaur, Paramdeep Singh, Sandeep Singh, Anjana Munshi.
      Genetic aberration including mutation in oncogenes and tumor suppressor genes transforms normal cells into tumor cells. Epigenetic modifications work concertedly with genetic factors in controlling cancer development. Histone acetyltransferases (HATs), histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and chromatin structure modifier are prospective epigenetic regulators. Specifically, HDACs are histone modifiers regulating the expression of genes implicated in cell survival, growth, apoptosis, and metabolism. The majority of HDACs are highly upregulated in cancer, whereas some have a varied function and expression in cancer progression. Distinct HDACs have a positive and negative role in controlling cancer progression. HDACs are also significantly involved in tumor cells acquiring metastatic and angiogenic potential in order to withstand the anti-tumor microenvironment. HDACs' role in modulating metabolic genes has also been associated with tumor development and survival. This review highlights and discusses the molecular mechanisms of HDACs by which they regulate cell survival, apoptosis, metastasis, invasion, stemness potential, angiogenesis, and epithelial to mesenchymal transitions (EMT) in tumor cells. HDACs are the potential target for anti-cancer drug development and various inhibitors have been developed and FDA approved for a variety of cancers. The primary HDAC inhibitors with proven anti-cancer efficacy have also been highlighted in this review.
    Keywords:  Angiogenesis; Cancer; Histone deacetylases; Metabolism; Metastasis; Stemness potential
    DOI:  https://doi.org/10.1007/s12032-022-01770-4
  5. Exp Oncol. 2022 08;44(2): 126-131
    TRANSCRIPTIONAL ANALYSIS OF ZINC-DEPENDENT HISTONE DEACETYLASES IN SEVERAL HUMAN CANCER CELLS.
    Li Yan, Zou Yefang, Chen Xiaoxue, He Bin.
      Histone deacetylases, especially zinc-dependent deacetylases HDACs, are among attractive drug targets for treating cancer in recent years.AIM: To explore the expression level of HDACs in several human cancer cell lines and examine the possible association between their expression and the sensitivity/resistance to the selective- or pan-HDAC inhibitors.
    MATERIALS AND METHODS: The RNA expression of 11 HDACs isoforms was assayed in HeLa, HepG2, AV3, HEK293, A549, and K562 cells by semiquantitative reverse transcription-polymerase chain reaction. The sensitivity/resistance of these cell lines to the pan- or selective- HDAC inhibitors was estimated by MTS assay.
    RESULTS: The relative transcription of HDACs genes demonstrated that members of Class I HDAC (HDAC1, 2 and 3) and members of Class II HDAC (HDAC4, 5, 6 and 7) had slight to significant levels of expression in cell lines under study with no dominant HDAC-subtype gene transcription. pan-HDAC inhibitor demonstrated superior antitumor activity compared to HDAC isoform-selective inhibitor.
    CONCLUSION: The absence of the dominant HDAC-subtype gene transcription in different human cancer cell lines explains the inferior efficacy of HDAC isoform-selective inhibitors as compared to pan-HDAC inhibitors.
  6. Pathol Res Pract. 2022 Aug 12. pii: S0344-0338(22)00315-6. [Epub ahead of print]238 154071
    Mutually exclusive expression of EZH2 and H3K27me3 in non-small cell lung carcinoma.
    Takafumi Onishi, Tsuyoshi Takashima, Masako Kurashige, Kenji Ohshima, Eiichi Morii.
      Enhancer of zeste homolog 2 (EZH2) epigenetically represses gene expression via trimethylation of lysine 27 on histone 3 (H3K27me3). Non-small cell carcinoma (NSCLC) has been reported to show high EZH2 and low H3K27me3 expression compared to normal lung tissues, but there are no studies examining the expression of EZH2 and H3K27me3 simultaneously with immunohistochemistry. In the present study, the expression of EZH2 and H3K27me3 was examined in surgically resected NSCLC. We enrolled 27 cases of squamous cell carcinoma (SCC), 73 cases of Lepidic, 77 of Papillary/Acinar, 51 of Solid, 31 of Micropapillary, and 12 of Mucinous subtypes of adenocarcinoma. First, we examined the expression of EZH2 and H3K27me3 in normal and metaplastic bronchial epithelium adjacent to NSCLC. Normal bronchial epithelium showed EZH2 expression in a limited number of basal cells and H3K27me3 expression in surface differentiated cells with cilia or mucus. In metaplastic bronchial epithelium, the number of EZH2-positive cells increased in multilayered basal cells, and H3K27me3-positive cells were observed in the superficial layer. Then, EZH2 and H3K27me3 expression was analyzed in NSCLC. Abundant EZH2 and rare H3K27me3 expression was detected in SCC, Papillary/Acinar, Solid and Micropapillary subtypes. In Mucinous subtype, EZH2 expression was hardly detected, and H3K27me3 expression was detected in almost all tumor cells. EZH2-expressing and H3K27me3-expressing tumor cells were similarly observed in Lepidic subtype, but double immunofluorescence revealed that EZH2 and H3K27me3 expression pattern was mutually exclusive. No co-expression of EZH2 and H3K27me3 was detected in all examined subtypes. To our knowledge, there have been no reports describing mutually exclusive expression pattern of EZH2 and H3K27me3.
    Keywords:  EZH2; Epigenetics; H3K27me3; Lung cancer; Metaplasia; Non-small cell lung carcinoma
    DOI:  https://doi.org/10.1016/j.prp.2022.154071
  7. Front Oncol. 2022 ;12 935877
    Chromatin Dynamics in Digestive System Cancer: Commander and Regulator.
    Zeru Li, Bangbo Zhao, Cheng Qin, Yuanyang Wang, Tianhao Li, Weibin Wang.
      Digestive system tumors have a poor prognosis due to complex anatomy, insidious onset, challenges in early diagnosis, and chemoresistance. Epidemiological statistics has verified that digestive system tumors rank first in tumor-related death. Although a great number of studies are devoted to the molecular biological mechanism, early diagnostic markers, and application of new targeted drugs in digestive system tumors, the therapeutic effect is still not satisfactory. Epigenomic alterations including histone modification and chromatin remodeling are present in human cancers and are now known to cooperate with genetic changes to drive the cancer phenotype. Chromatin is the carrier of genetic information and consists of DNA, histones, non-histone proteins, and a small amount of RNA. Chromatin and nucleosomes control the stability of the eukaryotic genome and regulate DNA processes such as transcription, replication, and repair. The dynamic structure of chromatin plays a key role in this regulatory function. Structural fluctuations expose internal DNA and thus provide access to the nuclear machinery. The dynamic changes are affected by various complexes and epigenetic modifications. Variation of chromatin dynamics produces early and superior regulation of the expression of related genes and downstream pathways, thereby controlling tumor development. Intervention at the chromatin level can change the process of cancer earlier and is a feasible option for future tumor diagnosis and treatment. In this review, we introduced chromatin dynamics including chromatin remodeling, histone modifications, and chromatin accessibility, and current research on chromatin regulation in digestive system tumors was also summarized.
    Keywords:  chromatin dynamics; clinical trials; digestive system tumor; epigenetics; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2022.935877
  8. Mol Cell. 2022 Aug 18. pii: S1097-2765(22)00704-3. [Epub ahead of print]82(16): 2925-2938
    Oncohistones: Exposing the nuances and vulnerabilities of epigenetic regulation.
    Michelle M Mitchener, Tom W Muir.
      Work over the last decade has uncovered a new layer of epigenetic dysregulation. It is now appreciated that somatic missense mutations in histones, the packaging agents of genomic DNA, are often associated with human pathologies, especially cancer. Although some of these "oncohistone" mutations are thought to be key drivers of cancer, the impacts of the majority of them on disease onset and progression remain to be elucidated. Here, we survey this rapidly expanding research field with particular emphasis on how histone mutants, even at low dosage, can corrupt chromatin states. This work is unveiling the remarkable intricacies of epigenetic control mechanisms. Throughout, we highlight how studies of oncohistones have leveraged, and in some cases fueled, the advances in our ability to manipulate and interrogate chromatin at the molecular level.
    DOI:  https://doi.org/10.1016/j.molcel.2022.07.008
  9. Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2207392119
    Inferring gene regulation from stochastic transcriptional variation across single cells at steady state.
    Anika Gupta, Jorge D Martin-Rufino, Thouis R Jones, Vidya Subramanian, Xiaojie Qiu, Emmanuelle I Grody, Alex Bloemendal, Chen Weng, Sheng-Yong Niu, Kyung Hoi Min, Arnav Mehta, Kaite Zhang, Layla Siraj, Aziz Al' Khafaji, Vijay G Sankaran, Soumya Raychaudhuri, Brian Cleary, Sharon Grossman, Eric S Lander.
      Regulatory relationships between transcription factors (TFs) and their target genes lie at the heart of cellular identity and function; however, uncovering these relationships is often labor-intensive and requires perturbations. Here, we propose a principled framework to systematically infer gene regulation for all TFs simultaneously in cells at steady state by leveraging the intrinsic variation in the transcriptional abundance across single cells. Through modeling and simulations, we characterize how transcriptional bursts of a TF gene are propagated to its target genes, including the expected ranges of time delay and magnitude of maximum covariation. We distinguish these temporal trends from the time-invariant covariation arising from cell states, and we delineate the experimental and technical requirements for leveraging these small but meaningful cofluctuations in the presence of measurement noise. While current technology does not yet allow adequate power for definitively detecting regulatory relationships for all TFs simultaneously in cells at steady state, we investigate a small-scale dataset to inform future experimental design. This study supports the potential value of mapping regulatory connections through stochastic variation, and it motivates further technological development to achieve its full potential.
    Keywords:  gene regulation; single-cell transcriptomics; transcriptional bursting
    DOI:  https://doi.org/10.1073/pnas.2207392119
  10. Int J Biochem Cell Biol. 2022 Aug 16. pii: S1357-2725(22)00123-6. [Epub ahead of print] 106278
    Mechanical stretch aggravates vascular smooth muscle cell apoptosis and vascular remodeling by downregulating EZH2.
    Hong-Yu Zhong, Chong Yuan, Xiao-Lin Liu, Qian-Qian Wang, Xiao Li, Ya-Chao Zhao, Xuan Li, Dong-Dong Liu, Teng-Fei Zheng, Mei Zhang.
      BACKGROUND: Enhancer of zeste homolog 2 (EZH2) was recently found to play an important role in cardiovascular disease. However, the role of EZH2 in vascular remodeling induced by mechanical stretch is poorly understood. The aim of the present work was to investigate the role of EZH2 in regulating smooth muscle cell function through mechanical stretch assays and to explore the underlying mechanisms.METHODS: WT C57BL/6J mice underwent sham surgery or abdominal aortic constriction. The level of EZH2 expression was determined by Western blotting and immunohistochemical staining. We demonstrated the thickness of vascular remodeling by HE staining. JASPAR was used to predict transcription factors that could affect EZH2. Chromatin immunoprecipitation was used to substantiate the DNAprotein interactions. Promoter luciferase assays were performed to demonstrate the activity of the transcription factors.
    RESULTS: We found that in vivo, AAC significantly reduced EZH2 protein levels in the thoracic aorta. Smooth muscle-specific overexpression of EZH2 was sufficient to attenuate the AAC-induced reduction in trimethylation of Lys-27 in histone 3 and thickening of the arterial media. Administration of GSK-J4 (an inhibitor of H3K27me3 demethylase) induced the same effects. In addition, we found that mechanical stretch regulated the expression of EZH2 through the Yes-associated protein (YAP)- transcriptional factor TEA domain 1 (TEAD) pathway. TEAD1 bound directly to the promoter of EZH2, and blocking the YAP-TEAD1 interaction inhibited EZH2 downregulation due to mechanical stretch.
    CONCLUSION: This study reveals that mechanical stretch downregulates EZH2 through the YAP-TEAD1 pathway, thereby aggravating smooth muscle cell apoptosis and vascular remodeling.
    Keywords:  EZH2; YAP-TEAD; apoptosis; mechanical stretch; smooth muscle cell
    DOI:  https://doi.org/10.1016/j.biocel.2022.106278
  11. Cell Cycle. 2022 Aug 18. 1-17
    Distinct osteogenic effect of different periosteum derived cells via Hippo-YAP cascade signaling.
    Tang Yufei, Wu Bingfeng, Liu Jiayi, Long Hu, Lai Wenli, Xiang Lin.
      Periosteum is expected for bone repairing due to excellent regenerative potential. PDCs are the main source of cells for promoting bone repair. However, PDCs from different sites have been confirmed to be site specific due to their distinct embryonic origin and the methods of bone formation. Hippo-YAP pathway is proved to play a critical role in fate decision of mesenchymal stem cells. The effect of Hippo-YAP on PDCs has not been reported so far. Hence, we aim to explore the differences of PDCs from mandible and femur along with their possible responses to YAP signaling. mPDCs and fPDCs were obtained and tested through flow cytometry for identification. Follow-up results illustrated mPDCs was cubic shape and with better proliferation while fPDCs preferred slender cell shape with worse cell viability compared with mPDCs. mPDCs was superior to fPDCs in ALP activity, related mRNA expression and calcium deposits in late stage. Interestingly, downregulation of YAP promoted the ALP activity, related mRNA expression and calcium deposits of fPDCs while hindered that of mPDCs in vitro. Moreover, implant animal model in mandible and femur were constructed for evaluation in vivo. Histological results were similar to the results in vitro. We speculate this may result from their different embryonic origin and the way of bone formation. Taken together, results available suggested that mPDCs may serve as more optimal seed cells for tissue engineering compared with fPDCs; however, considering their different response to YAP signaling, to ensure sufficient YAP expression in mPDCs and appropriate declining YAP expression in fPDCs may establish better osteogenesis.
    Keywords:  Hippo-YAP signaling; Implants; Osteogenesis; Periosteum derived cells; Site-pecific; Tissue engineering
    DOI:  https://doi.org/10.1080/15384101.2022.2111768
  12. ChemMedChem. 2022 Aug 19. e202100622
    Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni.
    Muhammad Murtaza Hassan, Abootaleb Sedighi, Olasunkanmi O Olaoye, Cécile Häberli, Annika Merz, Elizabeth Ramos-Morales, Elvin D de Araujo, Christophe Romier, Manfred Jung, Jennifer Keiser, Patrick T Gunning.
      Schistosomiasis is a prevalent yet neglected tropical parasitic disease caused by the Schistosoma genus of blood flukes. Praziquantel is the only currently available treatment, hence drug resistance poses a major threat. Recently, histone deacetylase 8 (HDAC8) selective inhibitors have been proposed as a viable treatment for schistosomiasis. Herein, we report the phenotypic screening of a focused library of small molecules of varying HDAC isozyme-inhibition profiles, including eight HDAC8 inhibitors with >10-fold selectivity in comparable functional inhibition assays and IC50 values against HDAC8<100 nM. HDAC8-selective inhibitors showed the lowest potency against Schistosoma mansoni newly transformed schistosomula (NTS). Pan-HDAC inhibitors MMH258, MMH259, and MMH373, as assessed by functional inhibition assays, with minimal or no-observed hHDAC8 and SmHDAC8 activities, were active against both NTS (MMH258, IC50 =1.5 μM; MMH259, IC50 =2.3 μM) and adult S. mansoni (MMH258, IC50 =2.1 μM; MMH373, IC50 =3.4 μM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities.
    Keywords:  HDAC inhibitors; HDAC8 selective; Schistosoma mansoni; epigenetic therapy; schistosomiasis
    DOI:  https://doi.org/10.1002/cmdc.202100622
  13. Gene. 2022 Aug 16. pii: S0378-1119(22)00640-0. [Epub ahead of print] 146821
    Pan-cancer gene expression analysis: Identification of deregulated autophagy genes and drugs to target them.
    Sree Karani Kondapuram, Mohane Selvaraj Coumar.
      Identifying suitable deregulated targets in autophagy pathway is essential for developing autophagy modulating cancer therapies. With this aim, we systematically analyzed the expression levels of genes that contribute to the execution of autophagy in 21 cancers. Deregulated genes for 21 cancers were analyzed using the level 3 mRNA data from TCGAbiolinks. A total of 574 autophagy genes were mapped to the deregulated genes across 21 cancers. PPI network, cluster analysis, gene enrichment, gene ontology, KEGG pathway, patient survival, protein expression and cMap analysis were performed. Among the autophagy genes, 260 were upregulated, and 43 were downregulated across pan-cancer. The upregulated autophagy genes - CDKN2A and BIRC5 - were the most frequent signatures in cancers and could be universal cancer biomarkers. Significant involvement of autophagy process was found in 8 cancers (CHOL, HNSC, GBM, KICH, KIRC, KIRP, LIHC and SARC). Fifteen autophagy hub genes (ATP6V0C, BIRC5, HDAC1, IL4, ITGB1, ITGB4, MAPK3, mTOR, cMYC, PTK2, SRC, TCIRG1, TP63, TP73 and ULK1) were found to be linked with patients survival and also expressed in cancer patients tissue samples, making them as potential drug targets for these cancers. The deregulated autophagy genes were further used to identify drugs Losartan, BMS-345541, Embelin, Abexinostat, Panobinostat, Vorinostat, PD-184352, PP-1, XMD-1150, Triplotide, Doxorubicin and Ouabain, which could target one or more autophagy hub genes. Overall, our findings shed light on the most frequent cancer-associated autophagy genes, potential autophagy targets and molecules for cancer treatment. These findings can accelerate autophagy modulation in cancer therapy.
    Keywords:  Autophagy; Biomarker; Drug-target network; Gene expression analysis; Pan-cancer; protein-protein interaction network
    DOI:  https://doi.org/10.1016/j.gene.2022.146821
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