Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation.

Zeda Zhang
Chuanli Zhou
Xiaoling Li
Spencer D Barnes
Su Deng
Elizabeth Hoover
Chi-Chao Chen
Young Sun Lee
Yanxiao Zhang
Choushi Wang
Lauren A Metang
Chao Wu
Carla Rodriguez Tirado
Nickolas A Johnson
John Wongvipat
Kristina Navrazhina
Zhen Cao
Danielle Choi
Chun-Hao Huang
Eliot Linton
Xiaoping Chen
Yupu Liang
Christopher E Mason
Elisa de Stanchina
Wassim Abida
Amaia Lujambio
Sheng Li, The Jackson Laboratory
Scott W Lowe
Joshua T Mendell
Venkat S Malladi
Charles L Sawyers
Ping Mu


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.