Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence [Tissue ChIP-Seq]

In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various stages of the disease. However, therapy resistance inevitably occurs and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. In addition, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 – from inactive chromatin binding sites towards active cis-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian rhythm core component ARNTL. Post-treatment ARNTL levels associated with poor outcome, and ARNTL suppression decreased cell growth in vitro. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy, and revealed an acquired dependency on circadian regulator ARNTL, a novel candidate therapeutic target. AR, FOXA1 and H3K27ac ChIP-seq data on primary prostate carcinomas before and after neoadjuvant enzalutamide therapy. The raw sequencing data cannot be stored with GEO due to patient privacy and was uploaded to the European Genome/Phenome Archive (EGAS00001006017). For tissue ChIP-seq and RNA-seq, the raw sequencing data cannot be stored with GEO due to patient privacy and had to be uploaded to the European Genome/Phenome Archive (ChIP-seq: EGAS00001006017, RNA-seq: EGAS00001006016).