Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of prostate cancer. mCRPC resists androgen receptor (AR) inhibitors by amplifying AR signaling or by evolving into therapy-resistant subtypes that do not depend on AR. Elucidation of the epigenetic underpinnings of these subtypes could provide important insights into the drivers of therapy resistance. In this study, we produced chromatin accessibility maps linked to the binding of lineage-specific transcription factors (TF) by performing ATAC sequencing on 70 mCRPC tissue biopsies integrated with transcriptome and whole genome sequencing. mCRPC had a distinct global chromatin accessibility profile linked to AR function. Analysis of TF occupancy across accessible chromatin revealed 203 TFs associated with mCRPC subtypes. Notably, ZNF263 was identified as a putative prostate cancer TF with a significant impact on gene activity in the double-negative (AR- neuroendocrine-) subtype, potentially activating MYC targets. Overall, this analysis of chromatin accessibility in mCRPC provides valuable insights into epigenetic changes that occur during progression to mCRPC.
Cancer research. 2024 Jul 11 [Epub ahead of print]
Raunak Shrestha, Lisa N Chesner, Meng Zhang, Stanley Zhou, Adam Foye, Arian Lundberg, Alana S Weinstein, Martin Sjöström, Xiaolin Zhu, Thaidy Moreno-Rodriguez, Haolong Li, Su C/Pcf West Coast Prostate Cancer Dream Team, Joshi J Alumkal, Rahul Aggarwal, Eric J Small, Mathieu Lupien, David A Quigley, Felix Y Feng
University of California San Francisco Medical Center, San Francisco, CA, United States., University of California, San Francisco, United States., University of California, San Francisco, San Francisco, United States., University of Toronto, Princess Margaret Cancer Center-University Health Network, Ontario Institute for Cancer Research, Toronto, Ontario, Canada., University of California, San Francisco, San Francisco, CA, United States., the Institute of Cancer Research and Royal Marsden Hospital, Sutton, United Kingdom., University of California - San Francisco School of Medicine, San Francisco, CA, United States., University of Michigan Medical School, Ann Arbor, MI, United States., UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, United States.