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.

Copyright © 2017 Elsevier B.V. All rights reserved.

Figures

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 p16INK4a 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.