Chromatin relaxation is a feature of advanced prostate cancer [expression]

Altered patterns of transcription factor (TF) binding are now accepted as a hallmark of many aggressive cancers including prostate and breast cancers1,2. This implies that underlying global changes in chromatin accessibility may drive cancer progression, as previously hypothesized3-5. In addition there are epigenetic readers such as bromodomain containing protein 4 (BRD4), which have been shown to associate with these TFs6-8 and also to contribute to aggressive cancers of many types8,9 including prostate cancer (PC)6,10. Here we show for the first time that formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIRE-seq) applied to human prostate tumors tissue can define castrate-resistant prostate cancer (CRPC) and can be used to inform the discovery of gene-level classifiers for therapy. In addition, we show that the androgen receptor (AR) overexpression alone is a primary driver for chromatin relaxation and that this effect can be reversed using bromodomain inhibitors. We also report that bromodomain-containing proteins (BRDs) are overexpressed in advanced CRPCs and that ATAD2 and BRD2 have prognostic value. In conclusion, this is the first study demonstrating a major impact of BRDs on chromatin accessibility in CRPC in patient samples. Consequently, targeting bromodomains provides a compelling rational for combination therapy in which BRD-mediated TF binding is enhanced or modified as cancer progresses. Expression profile of LNCaP and VCaP prostate cancer cell lines treated with synthetic androgen R1881 with or without concomitant treatment with the pan-BET bromodomain inhibitor JQ1. Total RNA of three biological replicates for each condition was extracted using the RNeasy kit (Qiagen), conditions are: 5h R1881, 5h R1881+JQ1, 12h R1881, 12h R1881+JQ1, 24h R1881, and 24h R1881+JQ1