Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation.
Document Type
Article
Publication Date
4-13-2020
Keywords
JGM
JAX Source
Cancer Cell 2020 Apr 13; 37:584-598.e11
Volume
37
Issue
4
First Page
584
Last Page
598
ISSN
1878-3686
PMID
32220301
DOI
https://doi.org/10.1016/j.ccell.2020.03.001
Abstract
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.
Recommended Citation
Zhang Z,
Zhou C,
Li X,
Barnes S,
Deng S,
Hoover E,
Chen C,
Lee Y,
Zhang Y,
Wang C,
Metang L,
Wu C,
Tirado C,
Johnson N,
Wongvipat J,
Navrazhina K,
Cao Z,
Choi D,
Huang C,
Linton E,
Chen X,
Liang Y,
Mason C,
de Stanchina E,
Abida W,
Lujambio A,
Li S,
Lowe S,
Mendell J,
Malladi V,
Sawyers C,
Mu P.
Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. Cancer Cell 2020 Apr 13; 37:584-598.e11