Androgen receptor splice variants bind to constitutively open chromatin and promote abiraterone-resistant growth of prostate cancer.

Androgen receptor (AR) splice variants (ARVs) are implicated in development of castration-resistant prostate cancer (CRPC). Upregulation of ARVs often correlates with persistent AR activity after androgen deprivation therapy (ADT). However, the genomic and epigenomic characteristics of ARV-dependent cistrome and the disease relevance of ARV-mediated transcriptome remain elusive. Through integrated chromatin immunoprecipitation coupled sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis, we identified ARV-preferential-binding sites (ARV-PBS) and a set of genes preferentially transactivated by ARVs in CRPC cells. ARVs preferentially bind to enhancers located in nucleosome-depleted regions harboring the full AR-response element (AREfull), while full-length AR (ARFL)-PBS are enhancers resided in closed chromatin regions containing the composite FOXA1-nnnn-AREhalf motif. ARV-PBS exclusively overlapped with AR binding sites in castration-resistant (CR) tumors in patients and ARV-preferentially activated genes were up-regulated in abiraterone-resistant patient specimens. Expression of ARV-PBS target genes, such as oncogene RAP2A and cell cycle gene E2F7, were significantly associated with castration resistance, poor survival and tumor progression. We uncover distinct genomic and epigenomic features of ARV-PBS, highlighting that ARVs are useful tools to depict AR-regulated oncogenic genome and epigenome landscapes in prostate cancer. Our data also suggest that the ARV-preferentially activated transcriptional program could be targeted for effective treatment of CRPC.

Nucleic acids research. 2018 Jan 04 [Epub ahead of print]

Yundong He, Ji Lu, Zhenqing Ye, Siyuan Hao, Liewei Wang, Manish Kohli, Donald J Tindall, Benyi Li, Runzhi Zhu, Liguo Wang, Haojie Huang

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Department of Urology, University of Kansas Medical Center, Kansas City, KS 66160, USA., Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.