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BRG1 knockdown inhibits proliferation through multiple cellular pathways in prostate cancer

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Giles, KA, Gould, CM, Achinge-Kawecka, J, Page, SG, Kafer, GR, Rogers, S, Luu, P-L, Cesare, AJ, Clark, SJ and Taberlay, PC ORCID: 0000-0002-5298-8730 2021 , 'BRG1 knockdown inhibits proliferation through multiple cellular pathways in prostate cancer' , Clinical Epigenetics, vol. 13, no. 1 , pp. 1-18 , doi: 10.1186/s13148-021-01023-7.

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Abstract

Background: BRG1 (encoded by SMARCA4) is a catalytic component of the SWI/SNF chromatin remodelling complex, with key roles in modulating DNA accessibility. Dysregulation of BRG1 is observed, but functionally uncharacterised, in a wide range of malignancies. We have probed the functions of BRG1 on a background of prostate cancer to investigate how BRG1 controls gene expression programmes and cancer cell behaviour.Results: Our investigation of SMARCA4 revealed that BRG1 is over-expressed in the majority of the 486 tumours from The Cancer Genome Atlas prostate cohort, as well as in a complementary panel of 21 prostate cell lines. Next, we utilised a temporal model of BRG1 depletion to investigate the molecular effects on global transcription programmes. Depleting BRG1 had no impact on alternative splicing and conferred only modest effect on global expression. However, of the transcriptional changes that occurred, most manifested as down-regulated expression. Deeper examination found the common thread linking down-regulated genes was involvement in proliferation, including several known to increase prostate cancer proliferation (KLK2, PCAT1 and VAV3). Interestingly, the promoters of genes driving proliferation were bound by BRG1 as well as the transcription factors, AR and FOXA1. We also noted that BRG1 depletion repressed genes involved in cell cycle progression and DNA replication, but intriguingly, these pathways operated independently of AR and FOXA1. In agreement with transcriptional changes, depleting BRG1 conferred G1 arrest.Conclusions: Our data have revealed that BRG1 promotes cell cycle progression and DNA replication, consistent with the increased cell proliferation associated with oncogenesis.

Item Type: Article
Authors/Creators:Giles, KA and Gould, CM and Achinge-Kawecka, J and Page, SG and Kafer, GR and Rogers, S and Luu, P-L and Cesare, AJ and Clark, SJ and Taberlay, PC
Keywords: BRG1, cancer, cell cycle, chromatin remodelling, DNA replication, gene expression, SMARCA4, transcription
Journal or Publication Title: Clinical Epigenetics
Publisher: BiomedCentral
ISSN: 1868-7075
DOI / ID Number: 10.1186/s13148-021-01023-7
Copyright Information:

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, (https://creativecommons.org/licenses/by/4.0/) which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

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