MUC1-C Oncoprotein Integrates a Program of EMT, Epigenetic Reprogramming and Immune Evasion in Human Carcinomas

Abstract

The MUC1 gene evolved in mammalian species to provide protection of epithelia. The transmembrane MUC1 C-terminal subunit (MUC1-C) signals stress to the interior of the epithelial cell and, when overexpressed as in most carcinomas, functions as an oncoprotein. MUC1-C induces the epithelial-mesenchymal transition (EMT) by activating the inflammatory NF-κB p65 pathway and, in turn, the EMT-transcriptional repressor ZEB1. Emerging evidence has indicated that MUC1-C drives a program integrating the induction of EMT with activation of stem cell traits, epigenetic reprogramming and immune evasion. This mini-review focuses on the potential importance of this MUC1-C program in cancer progression.

Keywords: BMI1; DNMTs; EMT; MUC1-C; PD-L1; epigenetics; immune evasion; tumor suppressor genes.

Figure 1. Activation of MUC1-C induces diverse pathways linked to cancer

A. The MUC1 protein undergoes autocleavage into the shed N-terminal (MUC1-N) and transmembrane C-terminal (MUC1-C) subunits. This nomenclature is used to denote positioning of the subunits and to distinguish them from genetic isoforms, which use Greek symbols; for example, ERα and ERβ, the PKC isoenzymes and PDGF receptors. MUC1-C forms homodimers in the response to stress and transformation that are mediated by a CQC motif in the cytoplasmic domain (highlighted with red bracket). In turn, MUC1-C homodimers are necessary for interactions with RTKs at the cell membrane mediated by galectin-3 bridges, import into the nucleus by an importin-β-mediated mechanism, and transport to the mitochondrial outer membrane by HSP70/HSP90. In the nucleus, MUC1-C forms complexes with transcription factors (TFs), such as NF-κB p65 and ZEB1, which drive EMT and epigenetic regulators. B. The MUC1-C cytoplasmic domain is a 72 aa intrinsically disordered protein that functions as a node for the integration of diverse signaling pathways. The CQC motif is a sensor of oxidative stress that is necessary for MUC1-C homodimerization and function. In addition, the MUC1-C CQC motif is targeted by the GO-203 inhibitor. Highlighted are selected phosphorylation sites, which regulate binding to the indicated effectors of downstream signaling pathways.

Figure 2. MUC1-C activates an autoinductive inflammatory circuit that drives EMT, invasion and self-renewal capacity

A. MUC1-C activates the inflammatory NF-κB pathway by interacting directly with TAK1, IKKs and NF-κB p65. MUC1-C promotes occupancy of NF-κB p65 on promoters of its target genes, including MUC1 itself, and drives their transcription. B. The MUC1-C→NF-κB p65 circuit activates the ZEB1 gene. In turn, MUC1-C binds to ZEB1 and promotes ZEB1-mediated repression of target genes, such as CRB3, encoding the CRB3 polarity factor, and miR-200c, which promotes EMT and invasion.

Figure 3. MUC1-C integrates EMT with epigenetic programming and immune evasion

A. The MUC1-C→NF-B p65 circuit activates transcription of the DNMT1 and DNMT3b, but not DNMT3a, genes and thereby regulates global DNA methylation patterns. The MUC1-C→NF-κB p65→DNMT1/3b pathway also induces DNA methylation of the CDH1 promoter in association with suppression of E-cadherin expression. In addition, MUC1-C induces BMI1 transcription by a MYC-dependent mechanism and increases BMI1 expression by ZEB1-mediated suppression of miR-200c. MUC1-C binds to BMI1 and promotes ubiquitinylation of H2A (H2AUb1) and suppression of the BMI1 target gene, CDKN2A, with downregulation of p16^INK4a expression. Activation of BMI1 has been associated with cancer progression as a result of increases in self-renewal capacity, stem-like cells and genomic instability. B. The MUC1-C program activates the NF-κB p65 circuit and in turn integrates induction of (i) ZEB1 and EMT, (ii) the epigenetic regulators DNMT1/3b and BIM1, and (iii) PD-L1, an effector of immune evasion.