MUC1-C activates polycomb repressive complexes and downregulates tumor suppressor genes in human cancer cells

Abstract

<p id="P2">The PRC2 and PRC1 complexes are aberrantly expressed in human cancers that have been linked with decreases in patient survival. MUC1-C is an oncoprotein that is overexpressed in diverse human cancers and is associated with a poor prognosis. Recent studies have supported a previously unreported function for MUC1-C in activating PRC2 and PRC1 in cancer cells. In the regulation of PRC2, MUC1-C (i) drives transcription of the <i>EZH2</i> gene, (ii) binds directly to EZH2, and (iii) enhances occupancy of EZH2 on target gene promoters with an increase in H3K27 trimethylation. Regarding PRC1, which is recruited to PRC2 sites in the hierarchical model, MUC1-C induces <i>BMI1</i> transcription, forms a complex with BMI1, and promotes H2A ubiquitylation. MUC1-C thereby contributes to the integration of PRC2- and PRC1-mediated repression of tumor suppressor genes, such as <i>CDH1</i>, <i>CDKN2A, PTEN</i> and <i>BRCA1.</i> Like PRC2 and PRC1, MUC1-C is associated with the epithelial-mesenchymal transition (EMT) program, the cancer stem cell (CSC) state, and the acquisition of anticancer drug resistance. In concert with these observations, targeting MUC1-C downregulates EZH2 and BMI1, inhibits EMT and the CSC state, and reverses drug resistance. These findings emphasize the significance of MUC1-C as a therapeutic target for inhibiting aberrant PRC function and reprogramming the epigenome in human cancers. </p>