Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation.
Cancer Cell 2020 Apr 13; 37:584-598.e11
Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.
Zhang, Zeda; Zhou, Chuanli; Li, Xiaoling; Barnes, Spencer D; Deng, Su; Hoover, Elizabeth; Chen, Chi-Chao; Lee, Young Sun; Zhang, Yanxiao; Wang, Choushi; Metang, Lauren A; Wu, Chao; Tirado, Carla Rodriguez; Johnson, Nickolas A; Wongvipat, John; Navrazhina, Kristina; Cao, Zhen; Choi, Danielle; Huang, Chun-Hao; Linton, Eliot; Chen, Xiaoping; Liang, Yupu; Mason, Christopher E; de Stanchina, Elisa; Abida, Wassim; Lujambio, Amaia; Li, Sheng; Lowe, Scott W; Mendell, Joshua T; Malladi, Venkat S; Sawyers, Charles L; and Mu, Ping, "Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation." (2020). Faculty Research 2020. 68.