Checkpoint kinase 2 regulates prostate cancer cell growth through physical interactions with the androgen receptor

We have previously demonstrated that CHK2 is a critical negative regulator of AR transcriptional activity, PCa cell growth, and androgen sensitivity. We have now uncovered that the AR directly interacts with CHK2, and ionizing radiation (IR) increases this interaction, which crests one hour after IR-induced DNA damage. This IR-induced increase in CHK2–AR interactions requires AR phosphorylation on both serine81 and serine308 and CHK2 kinase activity. Kinase-impaired CHK2 variants, including the K373E variant associated with 4.2% of PCa, blocked IR-induced CHK2–AR interactions. The destabilization of CHK2-AR interactions induced by the CHK2 variants impairs CHK2 function as a negative regulator of cell growth. CHK2 depletion in LNCaP cells increases transcription of DNAPK and RAD54 and increases clonogenic survival. The data support a model where CHK2 sequesters the AR through direct binding which in turn decreases AR transcription and leads to suppression of PCa cell growth.