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

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 LintonXiaoping 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

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)584-598.e11
JournalCancer Cell
Volume37
Issue number4
DOIs
StatePublished - Apr 13 2020

Keywords

  • CHD1
  • NR2F1
  • NR3C1 (GR)
  • POU3F2 (BRN2)
  • TBX2
  • antiandrogen resistantce
  • castration-resistant prostate cancer
  • chromatin remodeling
  • lineage plasticity
  • tumor heterogeneity

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Zhang, Z., Zhou, C., Li, X., Barnes, S. D., Deng, S., Hoover, E., Chen, C. C., Lee, Y. S., Zhang, Y., Wang, C., Metang, L. A., Wu, C., Tirado, C. R., Johnson, N. A., Wongvipat, J., Navrazhina, K., Cao, Z., Choi, D., Huang, C. H., ... Mu, P. (2020). Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. Cancer Cell, 37(4), 584-598.e11. https://doi.org/10.1016/j.ccell.2020.03.001