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AR phosphorylation and CHK2 kinase activity regulates IR-stabilized AR-CHK2 interaction and prostate cancer survival

Huy Q Ta1, Natalia Dworak1, Melissa L Ivey1

  • 1Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, United States.

Elife
|June 25, 2020
PubMed

Insights

Checkpoint kinase 2 (CHK2) directly binds androgen receptor (AR), suppressing prostate cancer growth. DNA damage enhances this interaction, but CHK2 mutations disrupt it, promoting cancer cell survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Checkpoint kinase 2 (CHK2) is a known negative regulator of androgen receptor (AR) transcriptional activity, prostate cancer (PCa) cell growth, and androgen sensitivity.
  • Previous studies established CHK2's role in regulating AR and PCa progression.

Purpose of the Study:

  • To investigate the direct interaction between AR and CHK2.
  • To elucidate the role of ionizing radiation (IR) in modulating AR-CHK2 interactions.
  • To determine the impact of CHK2 kinase activity and mutations on AR regulation and PCa cell growth.

Main Methods:

  • Co-immunoprecipitation assays to detect AR-CHK2 interactions.
  • Analysis of AR phosphorylation and CHK2 kinase activity.
  • Assessment of CHK2 mutant effects on AR-CHK2 binding and cell growth.
  • Evaluation of CHK2 depletion effects on DNA repair genes and cell survival.

Main Results:

  • AR directly interacts with CHK2, and this interaction is significantly increased by ionizing radiation (IR).
  • IR-induced AR-CHK2 interaction enhancement is dependent on AR phosphorylation and CHK2 kinase activity.
  • Prostate cancer-associated CHK2 mutants with reduced kinase activity show diminished IR-induced AR-CHK2 interactions, leading to impaired negative regulation of cell growth.
  • CHK2 depletion results in increased transcription of DNA repair genes (DNAPK, RAD54), enhanced clonogenic survival, and accelerated resolution of DNA double-strand breaks.

Conclusions:

  • CHK2 acts as a negative regulator of AR transcriptional activity and PCa cell proliferation by directly sequestering AR.
  • Disruption of AR-CHK2 interaction, through CHK2 mutation or loss of expression, leads to increased AR transcriptional activity and promotes cancer cell survival, particularly in response to DNA damage.
Keywords:
ARCHK2androgen receptorbiochemistrycancer biologychemical biologyhumanprostateprostate cancersignaling

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