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

当前位置： X-MOL 学术 › Cancer Cell › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation.
Cancer Cell ( IF 48.8 ) Pub Date : 2020-03-26 , DOI: 10.1016/j.ccell.2020.03.001
Zeda Zhang ₁ , Chuanli Zhou ₂ , Xiaoling Li ₂ , Spencer D Barnes ₃ , Su Deng ₂ , Elizabeth Hoover ₄ , Chi-Chao Chen ₅ , Young Sun Lee ₄ , Yanxiao Zhang ₆ , Choushi Wang ₂ , Lauren A Metang ₂ , Chao Wu ₄ , Carla Rodriguez Tirado ₂ , Nickolas A Johnson ₂ , John Wongvipat ₄ , Kristina Navrazhina ₇ , Zhen Cao ₈ , Danielle Choi ₄ , Chun-Hao Huang ₅ , Eliot Linton ₄ , Xiaoping Chen ₉ , Yupu Liang ₁₀ , Christopher E Mason ₁₁ , Elisa de Stanchina ₉ , Wassim Abida ₁₂ , Amaia Lujambio ₁₃ , Sheng Li ₁₄ , Scott W Lowe ₁₅ , Joshua T Mendell ₁₆ , Venkat S Malladi ₃ , Charles L Sawyers ₁₇ , Ping Mu ₁₈

Affiliation

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Bioinformatics Core Facility of the Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
Ludwig Institute for Cancer Research, La Jolla, CA, USA.
Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Center for Clinical and Translational Science, Rockefeller University, New York, NY 10065, USA.
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA; The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.

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.

中文翻译：

CHD1 的缺失通过染色质失调促进了对 AR 靶向治疗的抗性的异质机制。

转移性前列腺癌的特征是反复发生的基因组拷贝数改变，这些改变被认为会导致对激素治疗的抵抗。我们在前列腺癌中缺失的 730 个基因的体内小发夹 RNA (shRNA) 筛选中确定 CHD1 缺失是抗雄激素抗性的原因。ATAC-seq 和 RNA-seq 分析表明，CHD1 缺失导致开放和封闭染色质的全局变化以及相关的转录组变化。对这些数据的综合分析，连同基于 CRISPR 的功能筛选，确定了四种转录因子（NR3C1、POU3F2、NR2F1 和 TBX2），这些因子有助于抗雄激素抗性，并与非管腔谱系程序的相关激活有关。因此，CHD1 丢失导致染色质失调，

更新日期：2020-04-20

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11