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

Zeda Zhang1, Chuanli Zhou2, Xiaoling Li2

  • 1Human 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.

Cancer Cell
|March 30, 2020
PubMed

Insights

Chromatin changes from CHD1 loss in metastatic prostate cancer drive antiandrogen resistance. This leads to transcriptional plasticity, enabling resistance through multiple mechanisms involving key transcription factors.

Area of Science:

  • Oncology
  • Genomics
  • Epigenetics

Background:

  • Metastatic prostate cancer often develops resistance to hormone therapy.
  • Genomic copy number alterations are implicated in this therapy resistance.

Purpose of the Study:

  • To identify genetic drivers of antiandrogen resistance in prostate cancer.
  • To elucidate the molecular mechanisms by which CHD1 loss confers resistance.

Main Methods:

  • Conducted an in vivo small hairpin RNA (shRNA) screen of 730 deleted genes.
  • Performed ATAC-seq and RNA-seq analyses to assess chromatin and transcriptomic changes.
  • Utilized CRISPR-based functional screening for gene identification.

Main Results:

  • Identified CHD1 loss as a cause of antiandrogen resistance.
  • CHD1 loss induced global chromatin alterations and transcriptomic shifts.
  • Discovered four transcription factors (NR3C1, POU3F2, NR2F1, TBX2) mediating resistance via non-luminal lineage programs.

Conclusions:

  • CHD1 loss causes chromatin dysregulation in prostate cancer.
  • This dysregulation establishes transcriptional plasticity, facilitating antiandrogen resistance.
  • Resistance emerges through diverse mechanisms driven by specific transcription factors.
Keywords:
CHD1NR2F1NR3C1 (GR)POU3F2 (BRN2)TBX2antiandrogen resistantcecastration-resistant prostate cancerchromatin remodelinglineage plasticitytumor heterogeneity

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