PAR-Induced Harnessing of EZH2 to beta-Catenin: Implications for Colorectal Cancer

G-protein-coupled receptors (GPCRs) are involved in a wide array of physiological and disease functions, yet knowledge of their role in colon cancer stem cell maintenance is still lacking. In addition, the molecular mechanisms underlying GPCR-induced post-translational signaling regulation are poorly understood. Here, we find that protease-activated receptor 4 (PAR(4)) unexpectedly acts as a potent oncogene, inducing beta-catenin stability and transcriptional activity. Both PAR(4) and PAR(2) are able to drive the association of methyltransferase EZH2 with beta-catenin, culminating in beta-catenin methylation. This methylation on a lysine residue at the N-terminal portion of beta-catenin suppresses the ubiquitination of beta-catenin, thereby promoting PAR-induced beta-catenin stability and transcriptional activity. Indeed, EZH2 is found to be directly correlated with high PAR(4)-driven tumors, and is abundantly expressed in large tumors, whereas very little to almost none is expressed in small tumors. A truncated form of beta-catenin, increment N133 beta-catenin, devoid of lysine, as well as serine/threonine residues, exhibits low levels of beta-catenin and a markedly reduced transcriptional activity following PAR(4) activation, in contrast to wt beta-catenin. Our study demonstrates the importance of beta-catenin lysine methylation in terms of its sustained expression and function. Taken together, we reveal that PAR-induced post-transcriptional regulation of beta-catenin is centrally involved in colon cancer.