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Published VersionCC BY V4.0, Open Access
Journal article
BRG1 knockdown inhibits proliferation through multiple cellular pathways in prostate cancer
Clinical Epigenetics, Vol.13(1), pp.1-18
2021
PMID: 33596994
Abstract
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.
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.
Our data have revealed that BRG1 promotes cell cycle progression and DNA replication, consistent with the increased cell proliferation associated with oncogenesis.
Details
- Title
- BRG1 knockdown inhibits proliferation through multiple cellular pathways in prostate cancer
- Authors
- Katherine A Giles (Author) - Garvan Institute of Medical ResearchCathryn M Gould (Author) - Garvan Institute of Medical ResearchJoanna Achinger-Kawecka (Author) - Garvan Institute of Medical ResearchScott G Page (Author) - The University of SydneyGeorgia R Kafer (Author) - The University of SydneySamuel Rogers (Author) - The University of SydneyPhuc-Loi Luu (Author) - Garvan Institute of Medical ResearchAnthony J Cesare (Author) - The University of SydneySusan J Clark (Author) - Garvan Institute of Medical ResearchPhillippa C Taberlay (Author) - University of Tasmania
- Publication details
- Clinical Epigenetics, Vol.13(1), pp.1-18
- Publisher
- BioMed Central Ltd.
- Date published
- 2021
- DOI
- 10.1186/s13148-021-01023-7
- ISSN
- 1868-7083; 1868-7075
- PMID
- 33596994
- Copyright note
- This article is licensed under a Creative Commons Attribution 4.0 International License, 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. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
- Organisation Unit
- School of Health - Biomedicine; Australian Centre for Pacific Islands Research; University of the Sunshine Coast, Queensland; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99554708402621
- Output Type
- Journal article
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