近日，美国德克萨斯大学西南医学中心Ping Mu、纪念斯隆-凯特琳癌症中心Charles L. Sawyers等研究人员合作中取得进展。他们发现，CHD1丢失通过染色质失调促进对雄激素靶向治疗的耐药性。相关论文于2020年3月26日在线发表于国际学术期刊《癌细胞》。

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

Author: 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, Scott W. Lowe, Joshua T. Mendell, Venkat S. Malladi, Charles L. Sawyers, Ping Mu

Issue&Volume: 2020-03-26

Abstract: Metastatic prostate cancer is characterized by recurrent genomic copy number alterationsthat 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-seqand RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomicchanges. Integrative analysis of this data, together with CRISPR-based functionalscreening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2)that contribute to antiandrogen resistance, with associated activation of non-luminallineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptionalplasticity that enables the emergence of antiandrogen resistance through heterogeneousmechanisms.

DOI: 10.1016/j.ccell.2020.03.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30101-X