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

Abstract
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Abstract

We have previously demonstrated that checkpoint kinase 2 (CHK2) is a critical negative regulator of androgen receptor (AR) transcriptional activity, prostate cancer (PCa) cell growth, and androgen sensitivity. We have now uncovered that the AR directly interacts with CHK2 and ionizing radiation (IR) increases this interaction. This IR-induced increase in AR–CHK2 interactions requires AR phosphorylation and CHK2 kinase activity. PCa associated CHK2 mutants with impaired kinase activity reduced IR-induced AR–CHK2 interactions. The destabilization of AR–CHK2 interactions induced by CHK2 variants impairs CHK2 negative regulation of cell growth. CHK2 depletion increases transcription of DNAPK and RAD54, increases clonogenic survival, and increases resolution of DNA double strand breaks. The data support a model where CHK2 sequesters the AR through direct binding decreasing AR transcription and suppressing PCa cell growth. CHK2 mutation or loss of expression thereby leads to increased AR transcriptional activity and survival in response to DNA damage.

Data availability

Source data is available via the Open Science Framework https://osf.io/2bx5q/

The following data sets were generated

1. Gioeli D
(2020) AR_CHK2_Gioeli
Open Science Framework, 2bx5q.

https://osf.io/2bx5q/

Article and author information

Author details

Huy Q Ta

Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, United States

Competing interests
The authors declare that no competing interests exist.
Natalia Dworak

Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, United States

Competing interests
The authors declare that no competing interests exist.
Melissa L Ivey

Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, United States

Competing interests
The authors declare that no competing interests exist.
Devin G Roller

Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, United States

Competing interests
The authors declare that no competing interests exist.
Daniel Gioeli

Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, United States

For correspondence
dgioeli@virginia.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2284-8152

Funding

NIH Office of the Director (R01 CA178338)

Daniel Gioeli

Paul Mellon Urologic Cancer Institute

Daniel Gioeli

University of Virginia Cancer Center Patient and Friends

Daniel Gioeli

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.