bims-ectoca 2022-10-30 papers

Issue of 2022‒10‒30
six papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Subcell Biochem. 2022 ;100 473-502

Epigenetic Regulation Towards Acquired Drug Resistance in Cancer.

Therapy resistance remains the most challenging obstacle in cancer treatment. Substantial efforts and evidences have accumulated over decades suggesting not only genetic but non-genomic mechanisms underlying this adaptation of tumor cells. Alterations in epigenome can have a fundamental effect on cellular functions and response to stresses like anticancer therapy. This chapter discusses the principal mechanisms by which epigenetic modifications in the genome and transcriptome aid tumor cells toward acquisition of resistance to chemotherapy.

Keywords: Cancer; Chemoresistance; Chromatin remodeling; DNA methylation; Epigenetic modification; HDAC; Histone methylation; Histone ubiquitination; lncRNA; miRNA

DOI: https://doi.org/10.1007/978-3-031-07634-3_14

Biomolecules. 2022 Sep 24. pii: 1365. [Epub ahead of print]12(10):

Cisplatin Resistance: Genetic and Epigenetic Factors Involved.

Yuliannis Lugones, Pía Loren, Luis A Salazar.

Cisplatin (CDDP) is the drug of choice against different types of cancer. However, tumor cells can acquire resistance to the damage caused by cisplatin, generating genetic and epigenetic changes that lead to the generation of resistance and the activation of intrinsic resistance mechanisms in cancer cells. Among them, we can find mutations, alternative splicing, epigenetic-driven expression changes, and even post-translational modifications of proteins. However, the molecular mechanisms by which CDDP resistance develops are not clear but are believed to be multi-factorial. This article highlights a description of cisplatin, which includes action mechanism, resistance, and epigenetic factors involved in cisplatin resistance.

Keywords: cancer; cisplatin; drug resistance; epigenetics

DOI: https://doi.org/10.3390/biom12101365

Subcell Biochem. 2022 ;100 427-472

The Cross-Talk between Epigenetic Gene Regulation and Signaling Pathways Regulates Cancer Pathogenesis.

Snigdha Samanta, Rumpa Mahata, Manas Kumar Santra.

Cancer begins due to uncontrolled cell division. Cancer cells are insensitive to the signals that control normal cell proliferation. This uncontrolled cell division is due to the accumulation of abnormalities in different factors associated with the cell division, including different cyclins, cell cycle checkpoint inhibitors, and cellular signaling. Cellular signaling pathways are aberrantly activated in cancer mainly due to epigenetic regulation and post-translational regulation. In this chapter, the role of epigenetic regulation in aberrant activation of PI3K/AKT, Ras, Wnt, Hedgehog, Notch, JAK/STAT, and mTOR signaling pathways in cancer progression is discussed. The role of epigenetic regulators in controlling the upstream regulatory proteins and downstream effector proteins responsible for abnormal cellular signaling-mediated cancer progression is covered in this chapter. Similarly, the role of signaling pathways in controlling epigenetic gene regulation-mediated cancer progression is also discussed. We have tried to ascertain the current status of potential epigenetic drugs targeting several epigenetic regulators to prevent different cancers.

Keywords: Epigenetic Biomarkers; Epigenetic drugs; Hedgehog; Histone modification; JAK/STAT; MAPK; Notch; PI3K/AKT; Promoter hypermethylation; Ras; Wnt/β-catenin; mTOR

DOI: https://doi.org/10.1007/978-3-031-07634-3_13

PLoS One. 2022 ;17(10): e0274546

An integrated multi-omics analysis of topoisomerase family in pan-cancer: Friend or foe?

Xin Zhou, Guixiang Yao, Jin Zhang, Jiasheng Bian, Guanghao Li, Jianfeng Xu.

BACKGROUND: Topoisomerases are nuclear enzymes that get to the bottom of topological troubles related with DNA all through a range of genetic procedures. More and more studies have shown that topoisomerase-mediated DNA cleavage plays crucial roles in tumor cell death and carcinogenesis. There is however still a lack of comprehensive multi-omics studies related to topoisomerase family genes from a pan-cancer perspective.METHODS: In this study, a multiomics pan-cancer analysis of topoisomerase family genes was conducted by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from The Cancer Genome Atlas (TCGA), 481 small molecule drug response data from cancer therapeutics response portal (CTRP) as well as normal tissue data from Genotype-Tissue Expression (GTEx). Finally, overall activity-level analyses of topoisomerase in pan-cancers were performed by gene set variation analysis (GSVA), together with differential expression, clinical relevancy, immune cell infiltration and regulation of cancer-related pathways.
RESULTS: Dysregulated gene expression of topoisomerase family were related to genomic changes and abnormal epigenetic modifications. The expression levels of topoisomerase family genes could significantly impact cancer progression, intratumoral heterogeneity, alterations in the immunological condition and regulation of the cancer marker-related pathways, which in turn caused the differences in potential drugs sensitivity and the distinct prognosis of patients.
CONCLUSION: It was anticipated that topoisomerase family genes would become novel prognostic biomarkers for cancer patients and provide new insights for the diagnosis and treatment of tumors.

DOI: https://doi.org/10.1371/journal.pone.0274546

Front Cell Dev Biol. 2022 ;10 1007120

Emerin interacts with histone methyltransferases to regulate repressive chromatin at the nuclear periphery.

Nicholas Marano, James M Holaska.

X-Linked Emery-Dreifuss muscular dystrophy is caused by mutations in the gene encoding emerin. Emerin is an inner nuclear membrane protein important for repressive chromatin organization at the nuclear periphery. Myogenic differentiation is a tightly regulated process characterized by genomic reorganization leading to coordinated temporal expression of key transcription factors, including MyoD, Pax7, and Myf5. Emerin was shown to interact with repressive histone modification machinery, including HDAC3 and EZH2. Using emerin-null myogenic progenitor cells we established several EDMD-causing emerin mutant lines in the effort to understand how the functional interaction of emerin with HDAC3 regulates histone methyltransferase localization or function to organize repressive chromatin at the nuclear periphery. We found that, in addition to its interaction with HDAC3, emerin interacts with the histone methyltransferases EZH2 and G9a in myogenic progenitor cells. Further, we show enhanced binding of emerin HDAC3-binding mutants S54F and Q133H to EZH2 and G9a. Treatment with small molecule inhibitors of EZH2 and G9a reduced H3K9me2 or H3K27me3 throughout differentiation. EZH2 and G9a inhibitors impaired cell cycle withdrawal, differentiation commitment, and myotube formation in wildtype progenitors, while they had no effect on emerin-null progenitors. Interestingly, these inhibitors exacerbated the impaired differentiation of emerin S54F and Q133H mutant progenitors. Collectively, these results suggest the functional interaction between emerin and HDAC3, EZH2, and G9a are important for myogenic differentiation.

Keywords: EZH2; Emery-Dreifuss muscular dystrophy; G9a; emerin; myogenic differentiation; repressive chromatin

DOI: https://doi.org/10.3389/fcell.2022.1007120

Small. 2022 Oct 28. e2203515

Cell-Taxi: Mesenchymal Cells Carry and Transport Clusters of Cancer Cells.

Jana Zarubova, Mohammad Mahdi Hasani-Sadrabadi, Sam C P Norris, Fatemeh Sadat Majedi, Crystal Xiao, Andrea M Kasko, Song Li.

Cell clusters that collectively migrate from primary tumors appear to be far more potent in forming distant metastases than single cancer cells. A better understanding of the collective cell migration phenomenon and the involvement of various cell types during this process is needed. Here, an in vitro platform based on inverted-pyramidal microwells to follow and quantify the collective migration of hundreds of tumor cell clusters at once is developed. These results indicate that mesenchymal stromal cells (MSCs) or cancer-associated fibroblasts (CAFs) in the heterotypic tumor cell clusters may facilitate metastatic dissemination by transporting low-motile cancer cells in a Rac-dependent manner and that extracellular vesicles secreted by mesenchymal cells only play a minor role in this process. Furthermore, in vivo studies show that cancer cell spheroids containing MSCs or CAFs have faster spreading rates. These findings highlight the active role of co-traveling stromal cells in the collective migration of tumor cell clusters and may help in developing better-targeted therapies.

Keywords: circulating tumor cell clusters; collective cell migration; extracellular vesicles; micropatterned hydrogels; spheroid migration assay

DOI: https://doi.org/10.1002/smll.202203515