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

Cancer Cell. 2020 Apr 13;37(4):584-598.e11. doi: 10.1016/j.ccell.2020.03.001. Epub 2020 Mar 26.

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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Antagonists / pharmacology*
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Cell Proliferation
  • Chromatin / genetics*
  • Chromatin / metabolism
  • DNA Helicases / antagonists & inhibitors*
  • DNA Helicases / genetics
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic
  • High-Throughput Screening Assays
  • Humans
  • Male
  • Mice
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • RNA, Small Interfering / genetics*
  • Receptors, Androgen / chemistry*
  • Receptors, Androgen / genetics
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • AR protein, human
  • Androgen Antagonists
  • Biomarkers, Tumor
  • Chromatin
  • DNA-Binding Proteins
  • RNA, Small Interfering
  • Receptors, Androgen
  • Transcription Factors
  • DNA Helicases
  • CHD1 protein, human