PPARγ E3 ubiquitin ligase regulates MUC1-C oncoprotein stability.

MUC1-C oncoprotein is associated with colon, breast, ovarian, lung and pancreatic cancers. MUC1-C interacts with intracellular proteins to elicit signaling cascades that induce cell proliferation and tumor growth. Here we report that peroxisome proliferator-activated receptor gamma (PPARγ), an E3 ubiquitin ligase, is an inhibitor of MUC1-C-mediated cell proliferation. PPARγ does so by binding to and inducing MUC1-C proteasome-dependent degradation that was independent of PPARγ transcriptional activity. Lys134 residue was found to be critically important for PPARγ-mediated MUC1-C degradation, as it terminated MUC1-C-mediated cell proliferation. These findings demonstrate PPARγ induces MUC1-C ubiquitination and degradation that is critical to terminate MUC1-C signaling pathway-elicited cancer.