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 PKCα 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 PKCα expression. IHC analysis showed abnormal upregulation of PKCα in human primary prostate tumors. Interestingly, silencing PKCα 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 PKCα exerts a profound control of gene expression, particularly over genes and transcriptional networks associated with cell-cycle progression and E2F transcription factors. PKCα RNAi depletion from PC3 prostate cancer cells led to a reduction in the expression of proinflammatory cytokine and epithelial-to-mesenchymal transition (EMT) genes, as well as a prominent downregulation of the immune checkpoint ligand PD-L1. This PKCα-dependent gene expression profile was corroborated in silico using human prostate cancer databases. Our studies established PKCα 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 PKCα as a protumorigenic kinase in human prostate cancer provides strong rationale for the development of therapeutic approaches toward targeting PKCα or its effectors. Significance: PKCα was found to be aberrantly expressed in human prostate cancer. Silencing the expression of this kinase from aggressive prostate cancer cell lines reduces their proliferative, tumorigenic, and invasive properties. In addition, our findings implicate PKCα as a major node for transcriptional regulation of tumorigenic, inflammatory, and EMT networks in prostate cancer, highlighting its potential relevance as a therapeutic target.