BRD9 Is a Critical Regulator of Androgen Receptor Signaling and Prostate Cancer Progression

Abstract

Switch/sucrose-nonfermentable (SWI/SNF) chromatin-remodeling complexes are critical regulators of chromatin dynamics during transcription, DNA replication, and DNA repair. A recently identified SWI/SNF subcomplex termed GLTSCR1/1L-BAF (GBAF; or “noncanonical BAF”, ncBAF) uniquely contains bromodomain-containing protein BRD9 and glioma tumor suppressor candidate region 1 (GLTSCR1) or its paralog GLTSCR1-like (GLTSCR1L). Recent studies have identified a unique dependency on GBAF (ncBAF) complexes in synovial sarcoma and malignant rhabdoid tumors, both of which possess aberrations in canonical BAF (cBAF) and Polybromo-BAF (PBAF) complexes. Dependencies on GBAF in malignancies without SWI/SNF aberrations, however, are less defined. Here, we show that GBAF, particularly its BRD9 subunit, is required for the viability of prostate cancer cell lines in vitro and for optimal xenograft tumor growth in vivo. BRD9 interacts with androgen receptor (AR) and CCCTC-binding factor (CTCF), and modulates AR-dependent gene expression. The GBAF complex exhibits overlapping genome localization and transcriptional targets as bromodomain and extraterminal domain–containing (BET) proteins, which are established AR coregulators. Our results demonstrate that GBAF is critical for coordinating SWI/SNF–BET cooperation and uncover a new druggable target for AR-positive prostate cancers, including those resistant to androgen deprivation or antiandrogen therapies. Significance: Advanced prostate cancers resistant to androgen receptor antagonists are still susceptible to nontoxic BRD9 inhibitors, making them a promising alternative for halting AR signaling in progressed disease.

Molecular docking of SARS-COV-2 Spike epitope sequences identifies heterodimeric peptide-protein complex formation with human Zo-1, TLR8 and brain specific glial proteins

“…The use of md method is a new way to identify interaction between homologous as well as non-homologues proteins on the basis of atom-to-atom alignment profile between two interacting proteins. The computational approach with md has been used to demonstrate mode of action of natural compound as possible drug and therapeutics in cancer [22] , [23] . Recently, therapeutic importance of human antimicrobial peptide LL-37 for COVID has been analyzed by md methods [24] .…”

BRD9 Expression, Alteration, Survival And Pathway Analysis In 11 Independent Prostate Cancer Cohorts

“…Smith's paper on BRD9 in PCa suggests BRD9 could play a role in CRPC with BRD9 knockdown reducing the viability of AR-positive cell lines (including castration-resistant cell lines) [30]. Here, this cell line data was further characterised in 2053 PCa patients and did not suggest as promising a role, given BRD9 expression was similar in patients treated with and without second-generation antiandrogens.…”

“…BRD9 has not been well studied in prostate cancer to date with one paper published in December 2020 [30]. This paper showed that BRD9 inhibition and knockdown have overlapping effects, reducing AR-positive cell line growth both in vivo and in vitro.…”

“…plays an oncogenic role in many cancers with promise both as a diagnostic and prognostic biomarker [52][53][54]. The only paper on BRD9 and PCa used the TCGA evidence to show BRD9 worsened DFS, however did not investigate BRD9 as a biomarker in PCa [30].…”

“…The literature suggests that suggest BRD9 interacts with other genes in the SWI/SNF complex and cooperates with BET proteins [30,64].…”