dCas9-HDAC8-EGFP fusion enables epigenetic editing of breast cancer cells by H3K9 deacetylation.

Autor: Rahman MM; Department of Biology, University of Alabama at Birmingham, 902 14th Street South, Birmingham, AL 35294, USA., Tollefsbol TO; Department of Biology, University of Alabama at Birmingham, 902 14th Street South, Birmingham, AL 35294, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, 1802 6th Avenue South, Birmingham, AL 35294, USA; Integrative Center for Aging Research, University of Alabama at Birmingham, Birmingham, AL, USA; Nutrition Obesity Research Center, University of Alabama at Birmingham, 1675 University Blvd, Birmingham, AL 35294, USA; Comprehensive Diabetes Center, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, USA. Electronic address: trygve@uab.edu.
Jazyk: angličtina
Zdroj: European journal of cell biology [Eur J Cell Biol] 2024 Dec; Vol. 103 (4), pp. 151463. Date of Electronic Publication: 2024 Oct 18.
DOI: 10.1016/j.ejcb.2024.151463
Abstrakt: Epigenetic editing is thriving as a robust tool for manipulating transcriptional regulation and cell fate. Despite its regulatory role in gene downregulation, epigenetic editing with histone deacetylation has been sparsely studied, especially in the context of cancer. In this current study, we have reconstructed a dCas9-HDAC8-EGFP fusion to perform histone deacetylation on the promoter of the ESR1, TERT and CDKN1C genes for the first time in breast cancer cell lines MCF-7 and MDA-MB-231 as well as in HEK293T cells. Our results demonstrated that dCas9-HDAC8-EGFP in combination with appropriate gRNAs were able to downregulate the expression of the ESR1, TERT and CDKN1C genes transcriptionally by specifically depleting the H3K9ac level on the recruitment loci. The addition of histone deacetylase inhibitors was found to neutralize the outcomes of dCas9-HDAC8-EGFP-induced epigenetic editing. Furthermore, we observed a significant downregulation of full length ERα expression in epigenetically edited MCF-7 cells with consequential alteration in cellular response toward estradiol and tamoxifen treatment due to dCas9-HDAC8-EGFP mediated epigenetic editing of the ESR1 gene. Overall, dCas9-HDAC8-EGFP is a novel circuit that enabled downregulation of crucial genes with cellular outcome in breast cancer cells by preferentially inducing H3K9 deacetylation of specific promoter regions.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Trygve Tollefsbol reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze: MEDLINE
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