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CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive

Michael A Augello1, Deli Liu2, Lesa D Deonarine1

  • 1Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.

Cancer Cell
|April 2, 2019
PubMed

Insights

Chromatin remodeler CHD1 loss drives prostate cancer (PCa) by altering androgen receptor (AR) binding. Restoring CHD1 function may limit PCa progression by constraining AR activity.

Area of Science:

  • Molecular biology
  • Cancer research
  • Epigenetics

Background:

  • Chromatin remodeler CHD1 alterations are common in prostate cancer (PCa).
  • The tumor-suppressive role and tissue-specific loss of CHD1 in PCa are not well understood.
  • Androgen receptor (AR) signaling is crucial in PCa development and progression.

Purpose of the Study:

  • To investigate the tumor-suppressive functions of CHD1 in prostate cancer.
  • To understand the mechanisms by which CHD1 loss contributes to PCa.
  • To identify the role of CHD1 in regulating androgen receptor (AR) activity in prostate tissue.

Main Methods:

  • Chromatin immunoprecipitation sequencing (ChIP-seq) to map AR and CHD1 binding sites.
  • Analysis of gene expression changes upon CHD1 loss.
  • Prostate tumor formation studies in a murine model.

Main Results:

  • CHD1 occupies prostate-specific enhancers bound by AR and lineage-specific cofactors.
  • CHD1 loss leads to AR cistrome redistribution, mimicking oncogenic patterns in PCa.
  • AR cistrome shifts upon CHD1 loss are associated with a unique AR transcriptional signature enriched for pro-oncogenic pathways.
  • CHD1 loss drives tumor formation in the murine prostate.

Conclusions:

  • CHD1 acts as a tumor suppressor in the prostate.
  • CHD1 constrains AR binding and function, thereby limiting prostate cancer progression.
  • Understanding CHD1's role offers potential therapeutic strategies targeting AR signaling in PCa.
Keywords:
ARCHD1HOXB13androgen receptorchromatin remodelingcistrome reprogrammingepigeneticsinteractomeprostate cancerprostate cancer subclass

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