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

Abstract

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 (PAR4) unexpectedly acts as a potent oncogene, inducing β-catenin stability and transcriptional activity. Both PAR4 and PAR2 are able to drive the association of methyltransferase EZH2 with β-catenin, culminating in β-catenin methylation. This methylation on a lysine residue at the N-terminal portion of β-catenin suppresses the ubiquitination of β-catenin, thereby promoting PAR-induced β-catenin stability and transcriptional activity. Indeed, EZH2 is found to be directly correlated with high PAR4-driven tumors, and is abundantly expressed in large tumors, whereas very little to almost none is expressed in small tumors. A truncated form of β-catenin, ∆N133β-catenin, devoid of lysine, as well as serine/threonine residues, exhibits low levels of β-catenin and a markedly reduced transcriptional activity following PAR4 activation, in contrast to wt β-catenin. Our study demonstrates the importance of β-catenin lysine methylation in terms of its sustained expression and function. Taken together, we reveal that PAR-induced post-transcriptional regulation of β-catenin is centrally involved in colon cancer.

EZH2 is a key component of hepatoblastoma tumor cell growth

“…Canonical EZH2 downregulates β‐catenin repressors, thereby promoting hepatocellular carcinoma (HCC) cell proliferation 22–25 . However, EZH2 can also directly interact with β‐catenin to form a protein complex in other epithelial cancers 26–29 . Interestingly, simultaneous inhibition of the canonical and noncanonical functions of EZH2 in leukemia demonstrated a potent antineoplastic effect, indicating that both functions can play a role in cancer 30 …”

“…[22][23][24][25] However, EZH2 can also directly interact with βcatenin to form a protein complex in other epithelial cancers. [26][27][28][29] Interestingly, simultaneous inhibition of the canonical and noncanonical functions of EZH2 in leukemia demonstrated a potent antineoplastic effect, indicating that both functions can play a role in cancer. 30 Prior studies have implicated EZH2 in HB pathogenesis by demonstrating that shRNA-mediated inhibition of EZH2 limits the proliferation of HB cell lines Huh-6 and HepG2.…”