小发夹RNA
染色质
生物
前列腺癌
转录组
癌症研究
抗雄激素
染色质重塑
核糖核酸
遗传学
基因
癌症
基因表达
作者
Zeda Zhang,Chuanli Zhou,Xiaoling Li,Spencer Barnes,Su Deng,Elizabeth Hoover,Chi-Chao Chen,Young Sun Lee,Yanxiao Zhang,Choushi Wang,Lauren A. Metang,Chao Wu,Carla R. Tirado,Nickolas A. Johnson,John Wongvipat,Kristina Navrazhina,Zhen Cao,Danielle Choi,Chun‐Hao Huang,Eliot Linton
出处
期刊:Cancer Cell
[Cell Press]
日期:2020-03-26
卷期号:37 (4): 584-598.e11
被引量:140
标识
DOI:10.1016/j.ccell.2020.03.001
摘要
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.
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