研究揭示CHD1丟失促進雄激素治療耐藥性機制
作者：
小柯機器人發布時間：2020/3/28 21:48:02
近日，美國德克薩斯大學西南醫學中心Ping Mu、紀念斯隆-凱特琳癌症中心Charles L. Sawyers等研究人員合作中取得進展。他們發現，CHD1丟失通過染色質失調促進對雄激素靶向治療的耐藥性。相關論文於2020年3月26日在線發表於國際學術期刊《癌細胞》。
研究人員在前列腺癌中對730個基因進行體內小髮夾RNA（shRNA）篩選，並鑑定出CHD1丟失是抗雄激素耐藥性產生的原因。ATAC-seq和RNA-seq分析顯示，CHD1丟失導致開放和封閉染色質的整體變化以及相關的轉錄組變化。對該數據的綜合分析，再加上基於CRISPR的功能篩選，研究人員確定了四個轉錄因子（NR3C1、POU3F2、NR2F1和TBX2），它們有助於抗雄激素耐藥性產生，並伴隨著非腔細胞譜系程序的激活。因此，CHD1丟失會導致染色質失調，從而建立轉錄可塑性狀態，進而通過異源機制產生抗雄激素耐藥性。
據了解，轉移性前列腺癌的特徵是反覆的基因組拷貝數改變，這被認為會導致對激素治療的耐藥性。
附：英文原文
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