Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

Abstract

Summary Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here we show that chromatin accessibility defines castration resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

“…Importantly, overexpression of c-MYC has been shown to confer androgen-independent growth in PC cells (Bernard et al 2003). We confirmed these findings using an isogenic LNCaP cell-based model with enforced inducible MYC overexpression (Barfeld et al 2017). Using ChIP-exo sequencing, a variant of the ChIP-seq protocol that utilizes exonucleases for improved resolution of TF binding sites (Rhee & Pugh 2012), we further investigated the interplay of c-MYC with AR on chromatin and the transcriptional output in the context of c-MYC overexpression (Barfeld et al 2017).…”

“…An integrative analysis of chromatin structures, methylation and transcriptomes in patient samples, revealed that open chromatin proximal to gene transcriptional start sites (TSSs) was positively correlated with expression of those genes, while DNA methylation within 1 and 5 kb around the genes' TSSs were instead negatively correlated with gene expression Urbanucci et al 2017). This reinforces the notion that gene transcription is dictated by the chromatin structure and is in agreement with previous studies showing local DNA methylation to negatively correlate with transcript abundances (reviewed in Cedar & Bergman 2012).…”

Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma

“…These studies also revealed, that in women with estrogen receptor positive breast cancer (47) or endometrial cancer (48), low Brd4 expression is correlated with worsened survival. This is in contrast to men with prostate cancer, in whom low levels of Brd4 are associated with improved survival (34,48).…”

“…These exciting results suggest that differential sex-specific Brd4 localization may be responsible for the sex differences in GBM. Additionally, and given that (34,47,48). These studies also revealed, that in women with estrogen receptor positive breast cancer (47) or endometrial cancer (48), low Brd4 expression is correlated with worsened survival.…”

“…Brd4 is an epigenetic reader that binds acetylated histones H3 and H4 throughout the entire cell cycle and is known to be deregulated in numerous cancers (30). Brd4 is thought to play a central role in cancer by promoting epithelial-to-mesenchymal transition, stem cell-like conversion, and pluripotency (19,20,31), and the pharmacological inhibition of this protein has shown therapeutic activity in a number of different cancer models (28,(32)(33)(34)(35). To evaluate a potential role for Brd4 in mediating sex differences in GBM, we mapped Brd4 genomic localization in male and female GBM astrocytes (highly active Brd4-bound enhancers and typical Brd4-bound enhancers) using transposon Calling Cards (36,37) to identify enhancers differentially bound by Brd4.…”