bims-ectoca 2023-01-29 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023–01–29
fiveteen papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Mapping Multiple Factors-mediated Chromatin Interactions to Assess Dysregulation of Lung Cancer-related Genes.
Insights into the role of senescence in tumor dormancy: mechanisms and applications.
The role of cancer cell bioenergetics in dormancy and drug resistance.
Identification of therapeutic targets for osteosarcoma by integrating single-cell RNA sequencing and network pharmacology.
MUC1 promotes cancer stemness and predicts poor prognosis in osteosarcoma.
Cancer and meiotic gene expression: Two sides of the same coin?
Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer.
PERCC1, a new member of the Yap/TAZ/FAM181 transcriptional co-regulator family.
Pan-Cancer landscape of protein activities identifies drivers of signalling dysregulation and patient survival.
peaksat: an R package for ChIP-seq peak saturation analysis.
Epigenetic control of skin immunity.
β-actin mediated H3K27ac changes demonstrate the link between compartment switching and enhancer-dependent transcriptional regulation.
A truncated and catalytically inactive isoform of KDM5B histone demethylase accumulates in breast cancer cells and regulates H3K4 tri-methylation and gene expression.
Verteporfin reverses progestin resistance through YAP/TAZ-PI3K-Akt pathway in endometrial carcinoma.
Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis.

Genomics Proteomics Bioinformatics. 2023 Jan 23. pii: S1672-0229(23)00004-9. [Epub ahead of print]

Mapping Multiple Factors-mediated Chromatin Interactions to Assess Dysregulation of Lung Cancer-related Genes.

Yan Zhang, Jingwen Zhang, Wei Zhang, Mohan Wang, Shuangqi Wang, Yao Xu, Lun Zhao, Xingwang Li, Guoliang Li.

  Studies on the lung cancer genome are indispensable for developing a cure for lung cancer. Whole-genome resequencing, genome-wide association studies, and transcriptome sequencing have greatly improved our understanding of the cancer genome. However, dysregulation of long-range chromatin interactions in lung cancer remains poorly described. To better understand the three-dimensional (3D) genomic interaction features of the lung cancer genome, we used the A549 cell line as a model system and generated high-resolution chromatin interactions associated with RNA polymerase II (RNAPII), CCCTC-binding factor (CTCF), enhancer of zeste homolog 2 (EZH2), and histone 3 lysine 27 trimethylation (H3K27me3) using long-read chromatin interaction analysis by paired-end tag sequencing (ChIA-PET). Analysis showed that EZH2/H3K27me3-mediated interactions further repressed target genes, either through loops or domains, and their distributions along the genome were distinct from and complementary to those associated with RNAPII. Cancer-related genes were highly enriched with chromatin interactions, and chromatin interactions specific to the A549 cell line were associated with oncogenes and tumor suppressors, such as additional repressive interactions on FOXO4 and promoter-promoter interactions between NF1 and RNF135. Knockout of an anchor associated with chromatin interactions reversed the dysregulation of cancer-related genes, suggesting that chromatin interactions are essential for proper expression of lung cancer-related genes. These findings demonstrate the 3D landscape and gene regulatory relationships of the lung cancer genome.

Keywords:  3D genome; ChIA-PET; Chromatin interactions; Dysregulation; Lung cancer

DOI:  https://doi.org/10.1016/j.gpb.2023.01.004
Cancer Metastasis Rev. 2023 Jan 21.

Insights into the role of senescence in tumor dormancy: mechanisms and applications.

Valerie J DeLuca, Tareq Saleh.

  One of the most formidable challenges in oncology and tumor biology research is to provide an accurate understanding of tumor dormancy mechanisms. Dormancy refers to the ability of tumor cells to go undetected in the body for a prolonged period, followed by "spontaneous" escape. Various models of dormancy have been postulated, including angiogenic, immune-mediated, and cellular dormancy. While the former two propose mechanisms by which tumor growth may remain static at a population level, cellular dormancy refers to molecular processes that restrict proliferation at the cell level. Senescence is a form of growth arrest, during which cells undergo distinct phenotypic, epigenetic, and metabolic changes. Senescence is also associated with the development of a robust secretome, comprised of various chemokines and cytokines that interact with the surrounding microenvironment, including other tumor cells, stromal cells, endothelial cells, and immune cells. Both tumor and non-tumor cells can undergo senescence following various stressors, many of which are present during tumorigenesis and therapy. As such, senescent cells are present within forming tumors and in residual tumors post-treatment and therefore play a major role in tumor biology. However, the contributions of senescence to dormancy are largely understudied. Here, we provide an overview of multiple processes that have been well established as being involved in tumor dormancy, and we speculate on how senescence may contribute to these mechanisms.

Keywords:  Angiogenic; Autophagy; Cancer; Dormancy; Immunogenic; Polyploidy; Recurrence; Senescence

DOI:  https://doi.org/10.1007/s10555-023-10082-6
Cancer Metastasis Rev. 2023 Jan 25.

The role of cancer cell bioenergetics in dormancy and drug resistance.

Steven Tau, Todd W Miller.

  While anti-cancer drug treatments are often effective for the clinical management of cancer, these treatments frequently leave behind drug-tolerant persister cancer cells that can ultimately give rise to recurrent disease. Such persistent cancer cells can lie dormant for extended periods of time, going undetected by conventional clinical means. Understanding the mechanisms that such dormant cancer cells use to survive, and the mechanisms that drive emergence from dormancy, is critical to the development of improved therapeutic strategies to prevent and manage disease recurrence. Cancer cells often exhibit metabolic alterations compared to their non-transformed counterparts. An emerging body of evidence supports the notion that dormant cancer cells also have unique metabolic adaptations that may offer therapeutically targetable vulnerabilities. Herein, we review mechanisms through which cancer cells metabolically adapt to persist during drug treatments and develop drug resistance. We also highlight emerging therapeutic strategies to target dormant cancer cells via their metabolic features.

Keywords:  Cancer; Energy; Fatty acid; Glucose; Metabolism; Tumor

DOI:  https://doi.org/10.1007/s10555-023-10081-7
Front Pharmacol. 2022 ;13 1098800

Identification of therapeutic targets for osteosarcoma by integrating single-cell RNA sequencing and network pharmacology.

Yan Wang, Di Qin, Yiyao Gao, Yunxin Zhang, Yao Liu, Lihong Huang.

  Background: Osteosarcoma (OS) is a common primary tumor with extensive heterogeneity. In this study, we used single-cell RNA sequencing (scRNA-seq) and network pharmacology to analyze effective targets for Osteosarcoma treatment. Methods: The cell heterogeneity of the Osteosarcoma single-cell dataset GSE162454 was analyzed using the Seurat package. The bulk-RNA transcriptome dataset GSE36001 was downloaded and analyzed using the CIBERSORT algorithm. The key targets for OS therapy were determined using Pearson's correlation analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on key targets. The DeepDR algorithm was used to predict potential drugs for Osteosarcoma treatment. Molecular docking analysis was performed to verify the binding abilities of the predicted drugs and key targets. qRT-PCR assay was used to detect the expression of key targets in osteoblasts and OS cells. Results: A total of 21 cell clusters were obtained based on the GSE162454 dataset, which were labeled as eight cell types by marker gene tagging. Four cell types (B cells, cancer-associated fibroblasts (CAFs), endothelial cells, and plasmocytes) were identified in Osteosarcoma and normal tissues, based on differences in cell abundance. In total, 17 key targets were identified by Pearson's correlation analysis. GO and KEGG analysis showed that these 17 genes were associated with immune regulation pathways. Molecular docking analysis showed that RUNX2, OMD, and CD4 all bound well to vincristine, dexamethasone, and vinblastine. The expression of CD4, OMD, and JUN was decreased in Osteosarcoma cells compared with osteoblasts, whereas RUNX2 and COL9A3 expression was increased. Conclusion: We identified five key targets (CD4, RUNX2, OMD, COL9A3, and JUN) that are associated with Osteosarcoma progression. Vincristine, dexamethasone, and vinblastine may form a promising drug-target pair with RUNX2, OMD, and CD4 for Osteosarcoma treatment.

Keywords:  molecular docking; network pharmacology; osteosarcoma; single-cell RNA sequencing; therapeutic target

DOI:  https://doi.org/10.3389/fphar.2022.1098800
Pathol Res Pract. 2023 Jan 19. pii: S0344-0338(23)00029-8. [Epub ahead of print]242 154329

MUC1 promotes cancer stemness and predicts poor prognosis in osteosarcoma.

Jian Liu, Yixi Xu, Tianqi Xu, Yixiong Liu, Jin Liu, Jia Chai, Yanru Yang, Peizhen Hu, Mingyang Li, Qingge Jia, Chen Zhang.

  Osteosarcoma (OS) is one of the most common primary bone malignancy. Combining chemotherapy and surgical treatment significantly improved clinical outcomes for osteosarcoma patients. Osteosarcoma stem cells (OSCs) are often more malignant than differentiated cancer cells and are a key determinant of responses to chemotherapy and radiation therapy, therefore, the removal of OSCs could be an effective therapeutic strategy. Myxoprotein 1 (MUC1) is aberrantly overexpressed in many human cancers and it promotes cancer stemness through activation of pluripotency networks. In this study, we observed elevated MUC1 in osteosarcoma and a depressed prognosis in patients with high MUC1 expression profiles. Our observations also revealed that MUC1 promoted OS stemness and tumor metastasis both in vivo and in vitro. These data led us to hypothesize that MUC1 may be a therapeutic target for patients with OS.

Keywords:  Cancer stem cell; MUC1; Osteosarcoma; Prognosis; Stemness

DOI:  https://doi.org/10.1016/j.prp.2023.154329
Curr Top Dev Biol. 2023 ;pii: S0070-2153(22)00087-4. [Epub ahead of print]151 43-68

Cancer and meiotic gene expression: Two sides of the same coin?

Ieng Fong Sou, Geert Hamer, Wee-Wei Tee, Gerben Vader, Urszula Lucja McClurg.

  Meiosis increases genetic diversity in offspring by generating genetically unique haploid gametes with reshuffled chromosomes. This process requires a specialized set of meiotic proteins, which facilitate chromosome recombination and segregation. However, re-expression of meiotic proteins in mitosis can have catastrophic oncogenic consequences and aberrant expression of meiotic proteins is a common occurrence in human tumors. Mechanistically, re-activation of meiotic genes in cancer promotes oncogenesis likely because cancers-conversely to healthy mitosis-are fueled by genetic instability which promotes tumor evolution, and evasion of immune response and treatment pressure. In this review, we explore similarities between meiotic and cancer cells with a particular focus on the oncogenic activation of meiotic genes in cancer. We emphasize the role of histones and their modifications, DNA methylation, genome organization, R-loops and the availability of distal enhancers.

Keywords:  Cancer; Cancer testis antigen; Chromatin; Germ cell cancer gene; Meiosis; R-loop; Synaptonemal complex; TAD; Topologically associated domain; Transcription

DOI:  https://doi.org/10.1016/bs.ctdb.2022.06.002
J Med Chem. 2023 Jan 24.

Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer.

Qiangsheng Zhang, Xinyi Chen, Jiaying Cao, Wan Yang, Guoquan Wan, Qiang Feng, Shuyan Zhou, Hongling Yang, Ningyu Wang, Zhihao Liu, Hongtao Xiao, Yongxia Zhu, Luoting Yu.

Enhancer of zeste homologue 2 (EZH2) is the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2), which plays an important role in post-translational modifications of histones. In this study, we designed and synthesized a new series EZH2 covalent inhibitors that have rarely been reported. Biochemical studies and mass spectrometry provide information that SKLB-03220 could covalently bind to the S-adenosylmethionine (SAM) pocket of EZH2. Besides, SKLB-03220 was highly potent for EZH2MUT, while exhibiting weak activities against other tested histone methyltransferases (HMTs) and kinases. Moreover, SKLB-03220 displayed noteworthy potency against ovarian cancer cell lines and continuously abolished H3K27me3 after washing out. Furthermore, oral administration of SKLB-03220 significantly inhibited tumor growth in PA-1 xenograft model without obvious adverse effects. Taken together, SKLB-03220 is a potent, selective EZH2 covalent inhibitor with noteworthy anticancer efficacy both in vitro and in vivo.

DOI: https://doi.org/10.1021/acs.jmedchem.2c01370
Bioinform Adv. 2022 ;2(1): vbac008

PERCC1, a new member of the Yap/TAZ/FAM181 transcriptional co-regulator family.

Luis Sanchez-Pulido, Siyang Jia, Carsten Gram Hansen, Chris P Ponting.

Motivation: Disrupted PERCC1 gene expression causes an intractable congenital diarrhoea in infants. However, this gene's molecular mechanism is unknown and no homologous proteins have been reported.
Results: Our detailed evolutionary analysis of PERCC1 sequence reveals it to be a previously unappreciated member of the YAP/TAZ/FAM181 family of homologous transcriptional regulators. Like YAP and TAZ, PERCC1 likely interacts with DNA via binding to TEA/ATTS domain transcription factors (TEADs) using its conserved interface-2 and -3 sequences. We compare the expression patterns of PERCC1 with those of YAP, TAZ, TEADs. Our report provides the identification and first in-depth bioinformatic analysis of a YAP/TAZ homologue, and a likely new regulator of the YAP/TAZ-TEAD transcriptional complex.
Availability and implementation: The data underlying this article are available in UniProt Database.
Supplementary information: Supplementary data are available at Bioinformatics Advances online.

DOI: https://doi.org/10.1093/bioadv/vbac008
Mol Syst Biol. 2023 Jan 23. e10631

Pan-Cancer landscape of protein activities identifies drivers of signalling dysregulation and patient survival.

Abel Sousa, Aurelien Dugourd, Danish Memon, Borgthor Petursson, Evangelia Petsalaki, Julio Saez-Rodriguez, Pedro Beltrao.

  Genetic alterations in cancer cells trigger oncogenic transformation, a process largely mediated by the dysregulation of kinase and transcription factor (TF) activities. While the mutational profiles of thousands of tumours have been extensively characterised, the measurements of protein activities have been technically limited until recently. We compiled public data of matched genomics and (phospho)proteomics measurements for 1,110 tumours and 77 cell lines that we used to estimate activity changes in 218 kinases and 292 TFs. Co-regulation of kinase and TF activities reflects previously known regulatory relationships and allows us to dissect genetic drivers of signalling changes in cancer. We find that loss-of-function mutations are not often associated with the dysregulation of downstream targets, suggesting frequent compensatory mechanisms. Finally, we identified the activities most differentially regulated in cancer subtypes and showed how these can be linked to differences in patient survival. Our results provide broad insights into the dysregulation of protein activities in cancer and their contribution to disease severity.

Keywords:  adaptation; cancer genomics; cell signalling; phosphoproteomics; protein activities

DOI:  https://doi.org/10.15252/msb.202110631
BMC Genomics. 2023 Jan 25. 24(1): 43

peaksat: an R package for ChIP-seq peak saturation analysis.

Joseph R Boyd, Cong Gao, Kathleen Quinn, Andrew Fritz, Janet Stein, Gary Stein, Karen Glass, Seth Frietze.

   BACKGROUND: Epigenomic profiling assays such as ChIP-seq have been widely used to map the genome-wide enrichment profiles of chromatin-associated proteins and posttranslational histone modifications. Sequencing depth is a key parameter in experimental design and quality control. However, due to variable sequencing depth requirements across experimental conditions, it can be challenging to determine optimal sequencing depth, particularly for projects involving multiple targets or cell types.
RESULTS: We developed the peaksat R package to provide target read depth estimates for epigenomic experiments based on the analysis of peak saturation curves. We applied peaksat to establish the distinctive read depth requirements for ChIP-seq studies of histone modifications in different cell lines. Using peaksat, we were able to estimate the target read depth required per library to obtain high-quality peak calls for downstream analysis. In addition, peaksat was applied to other sequence-enrichment methods including CUT&RUN and ATAC-seq.
CONCLUSION: peaksat addresses a need for researchers to make informed decisions about whether their sequencing data has been generated to an adequate depth and subsequently sufficient meaningful peaks, and failing that, how many more reads would be required per library. peaksat is applicable to other sequence-based methods that include calling peaks in their analysis.

Keywords:  ChIP-Seq; Peak saturation; Read depth estimate

DOI:  https://doi.org/10.1186/s12864-023-09109-7
Immunol Med. 2023 Jan 27. 1-7

Epigenetic control of skin immunity.

Sayaka Shibata.

  Epigenetics has been well understood for its role in cell development; however, it is now known to regulate many processes involved in immune cell activation in a variety of cells. The skin maintains homeostasis via crosstalk between immune and non-immune cells. Disruption of normal epigenetic regulation in these cells may alter the transcription of immune-regulatory factors and affect the immunological balance in the skin. This review summarizes recent evidence for the epigenetic regulation of skin immunity. Much of what is known about epigenetic involvement in skin immunity is associated with DNA methylation. This review focuses on epigenetic regulation of histone modification and chromatin remodeling and describes their role in the transcriptional regulation of immune-regulatory factors. While much is still unknown regarding the regulation of skin immunity via histone modification or chromatin remodeling, these processes may underlie the pathogenesis of chronic cutaneous immune disorders.

Keywords:  Epigenetics; chromatin remodeling; histone modification; skin immunity

DOI:  https://doi.org/10.1080/25785826.2023.2170087
Genome Biol. 2023 Jan 25. 24(1): 18

β-actin mediated H3K27ac changes demonstrate the link between compartment switching and enhancer-dependent transcriptional regulation.

Syed Raza Mahmood, Nadine Hosny El Said, Kristin C Gunsalus, Piergiorgio Percipalle.

   BACKGROUND: Recent work has demonstrated that three-dimensional genome organization is directly affected by changes in the levels of nuclear cytoskeletal proteins such as β-actin. The mechanisms which translate changes in 3D genome structure into changes in transcription, however, are not fully understood. Here, we use a comprehensive genomic analysis of cells lacking nuclear β-actin to investigate the mechanistic links between compartment organization, enhancer activity, and gene expression.
RESULTS: Using HiC-Seq, ATAC-Seq, and RNA-Seq, we first demonstrate that transcriptional and chromatin accessibility changes observed upon β-actin loss are highly enriched in compartment-switching regions. Accessibility changes within compartment switching genes, however, are mainly observed in non-promoter regions which potentially represent distal regulatory elements. Our results also show that β-actin loss induces widespread accumulation of the enhancer-specific epigenetic mark H3K27ac. Using the ABC model of enhancer annotation, we then establish that these epigenetic changes have a direct impact on enhancer activity and underlie transcriptional changes observed upon compartment switching. A complementary analysis of fibroblasts undergoing reprogramming into pluripotent stem cells further confirms that this relationship between compartment switching and enhancer-dependent transcriptional change is not specific to β-actin knockout cells but represents a general mechanism linking compartment-level genome organization to gene expression.
CONCLUSIONS: We demonstrate that enhancer-dependent transcriptional regulation plays a crucial role in driving gene expression changes observed upon compartment-switching. Our results also reveal a novel function of nuclear β-actin in regulating enhancer function by influencing H3K27 acetylation levels.

Keywords:  3D genome organization; Enhancer regulation; Nuclear actin; Transcriptional regulation

DOI:  https://doi.org/10.1186/s13059-023-02853-9
Cancer Gene Ther. 2023 Jan 26.

A truncated and catalytically inactive isoform of KDM5B histone demethylase accumulates in breast cancer cells and regulates H3K4 tri-methylation and gene expression.

Elena Di Nisio, Valerio Licursi, Cecilia Mannironi, Valentina Buglioni, Alessandro Paiardini, Giulia Robusti, Roberta Noberini, Tiziana Bonaldi, Rodolfo Negri.

KDM5B histone demethylase is overexpressed in many cancers and plays an ambivalent role in oncogenesis, depending on the specific context. This ambivalence could be explained by the expression of KDM5B protein isoforms with diverse functional roles, which could be present at different levels in various cancer cell lines. We show here that one of these isoforms, namely KDM5B-NTT, accumulates in breast cancer cell lines due to remarkable protein stability relative to the canonical PLU-1 isoform, which shows a much faster turnover. This isoform is the truncated and catalytically inactive product of an mRNA with a transcription start site downstream of the PLU-1 isoform, and the consequent usage of an alternative ATG for translation initiation. It also differs from the PLU-1 transcript in the inclusion of an additional exon (exon-6), previously attributed to other putative isoforms. Overexpression of this isoform in MCF7 cells leads to an increase in bulk H3K4 methylation and induces derepression of a gene cluster, including the tumor suppressor Cav1 and several genes involved in the interferon-alpha and -gamma response. We discuss the relevance of this finding considering the hypothesis that KDM5B may possess regulatory roles independent of its catalytic activity.

DOI: https://doi.org/10.1038/s41417-022-00584-w
Cell Death Discov. 2023 Jan 25. 9(1): 30

Verteporfin reverses progestin resistance through YAP/TAZ-PI3K-Akt pathway in endometrial carcinoma.

Lina Wei, Xiaohong Ma, Yixin Hou, Tianyi Zhao, Rui Sun, Chunping Qiu, Yao Liu, Ziyi Qiu, Zhiming Liu, Jie Jiang.

Progestin resistance is a problem for patients with endometrial carcinoma (EC) who require conservative treatment with progestin, and its underlying mechanisms remain unclear. YAP and TAZ (YAP/TAZ), downstream transcription coactivators of Hippo pathway, promote viability, metastasis and also drug resistance of malignant tumors. According to our microarray analysis, YAP/TAZ were upregulated in progestin resistant IshikawaPR cell versus progestin sensitive Ishikawa cell, which implied that YAP/TAZ may be a vital promotor of resistance to progestin. We found YAP/TAZ had higher expression levels among the resistant tissues than sensitive tissues. In addition, knocking down YAP/TAZ decreased cell viability, inhibited cell migration and invasion and increased the sensitivity of IshikawaPR cell to progestin. On the contrary, overexpression of YAP/TAZ increased cell proliferation, metastasis and promoted progestin resistance. We also confirmed YAP/TAZ were involved in progestin resistant process by regulating PI3K-Akt pathway. Furthermore, Verteporfin as an inhibitor of YAP/TAZ could increase sensitivity of IshikawaPR cells to progestin in vivo and in vitro. Our study for the first time indicated that YAP/TAZ play an important role in progestin resistance by regulating PI3K-Akt pathway in EC, which may provide ideas for clinical targeted therapy of progestin resistance.

DOI: https://doi.org/10.1038/s41420-023-01319-y
Cell Commun Signal. 2023 Jan 23. 21(1): 22

Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis.

Tao Zhang, Ruiting Hu, Yan Wang, Shuai Guo, Zhimin Wu, Junfeng Liu, Chunyang Han, Changwei Qiu, Ganzhen Deng.

  The integrity of the structure and function of the endometrium is essential for the maintenance of fertility. However, the repair mechanisms of uterine injury remain largely unknown. Here, we showed that the disturbance of mechanical cue homeostasis occurs after uterine injury. Applying a multimodal approach, we identified YAP as a sensor of biophysical forces that drives endometrial regeneration. Through protein activation level analysis of the combinatorial space of mechanical force strength and of the presence of particular kinase inhibitors and gene silencing reagents, we demonstrated that mechanical cues related to extracellular matrix rigidity can turn off the Rap1a switch, leading to the inactivation of ARHGAP35and then induced activation of RhoA, which in turn depends on the polymerization of the agonist protein F-actin to activate YAP. Further study confirmed that mechanotransduction significantly accelerates remodeling of the uterus by promoting the proliferation of endometrial stromal cells in vitro and in vivo. These studies provide new insights into the dynamic regulatory mechanisms behind uterine remodeling and the function of mechanotransduction. Video Abstract.

Keywords:  ECM stiffness; Hippo-YAP; Mechanotransduction; Rap1a; Uterine repair

DOI:  https://doi.org/10.1186/s12964-022-01018-8