Protein kinase C alpha is a central node for tumorigenic transcriptional networks in human prostate cancer

Abstract

Aberrant expression of protein kinase C (PKC) isozymes is a hallmark of cancer. The different members of the PKC family control cellular events associated with cancer development and progression. Whereas the classical/conventional PKC isozyme has been linked to tumor suppression in most cancer types, here we demonstrate that this kinase is required for the mitogenic activity of aggressive human prostate cancer cells displaying aberrantly high PKC expression. Immunohistochemical analysis showed abnormal up-regulation of PKC in human primary prostate tumors. Interestingly, silencing PKC expression from aggressive prostate cancer cells impairs cell cycle progression, proliferation and invasion, as well as their tumorigenic activity in a mouse xenograft model. Mechanistic analysis revealed that PKC exerts a profound control of gene expression, particularly over genes and transcriptional networks associated with cell cycle progression and E2F transcription factors. PKC RNAi depletion from PC3 prostate cancer cells led to reduced expression of pro-inflammatory cytokine and epithelial-to-mesenchymal transition (EMT) genes, as well as a prominent down-regulation in the expression of the immune checkpoint ligand PD-L1. This PKC-dependent gene expression profile was corroborated in a human prostate cancer database. Our studies established PKC as a multifunctional kinase that plays pleiotropic roles in prostate cancer, particularly by controlling genetic networks associated with tumor growth and progression. The identification of PKC as a pro-tumorigenic kinase in human prostate cancer provides strong rationale for developing therapeutic approaches towards targeting PKC or its effectors. IMPLICATIONSOur findings implicate PKC as a major node for transcriptional regulation of tumorigenic pathways in prostate cancer.