AR phosphorylation and CHK2 kinase activity regulates IR stabilized AR-CHK2 interaction and prostate cancer survival
- University of Virginia, United States
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/
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Author details
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
© 2020, Ta et al.
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.
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AR phosphorylation and CHK2 kinase activity regulates IR stabilized AR-CHK2 interaction and prostate cancer survival
eLife 9:e51378.
https://doi.org/10.7554/eLife.51378
