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.
Cancer cell. 2020 Mar 26 [Epub]
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
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. Electronic address: ., 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. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/32220301