| MYC is frequently overexpressed in many human malignancies including prostate cancer. MYC accumulation is tightly regulated through transcriptional and post-translational mechanisms. Here, we demonstrate that a complex MYC/Protein Kinase A (PKA) signaling loop functions in prostate cancer cells. We show that MYC up-regulates Protein Kinase A Catalytic subunit ss (PKACss) transcription in human prostate cancer cells and mouse prostate cancers. We further demonstrate that PKA positively regulates MYC by phosphorylating Ser279, thereby priming phosphorylation by Polo-like kinase 1 at Ser281 and protecting MYC from degradation. Consistent with this, brief pharmacologic pan-PKA inhibition diminishes MYC level. Paradoxically however, prolonged Protein Kinase A Catalytic subunit alpha (PKACalpha), but not PKACss, knockdown increases MYC mRNA and protein levels, linking transcriptional repression of MYC with PKAC alpha activity, and revealing distinct functional roles among PKA catalytic isoforms in MYC regulation. We demonstrate that this effect stems from differential substrate selectivity among PKA isoforms, providing a mechanistic understanding of differential MYC regulation by PKA. Our observations establish PKA as a viable therapeutic target in MYC-overexpressing cancers, but highlight the risk of global PKA inhibition, underscoring the need to develop advanced inhibition strategies to disrupt specific kinase/substrate interactions. |
