Chronic activation of MUC1-C in wound repair promotes progression to cancer stem cells

Abstract

The mucin 1 (MUC1) gene emerged in mammals to afford protection of barrier epithelial tissues from the external environment. MUC1 encodes a transmembrane C-terminal (MUC1-C) subunit that is activated by loss of homeostasis and induces inflammatory, proliferative, and remodeling pathways associated with wound repair. As a consequence, chronic activation of MUC1-C promotes lineage plasticity, epigenetic reprogramming, and carcinogenesis. In driving cancer progression, MUC1-C is imported into the nucleus, where it induces NF-κB inflammatory signaling and the epithelial-mesenchymal transition (EMT). MUC1-C represses gene expression by activating (i) DNA methyltransferase 1 (DNMT1) and DNMT3b, (ii) Polycomb Repressive Complex 1 (PRC1) and PRC2, and (iii) the nucleosome remodeling and deacetylase (NuRD) nucleosome complex. PRC1/2-mediated gene repression is counteracted by the SWI/SNF chromatin remodeling complexes. MUC1-C activates the SWI/SNF BAF and PBAF complexes in cancer stem cell (CSC) models with the induction of genome-wide differentially accessible regions and expressed genes. MUC1-C regulates chromatin accessibility of enhancer-like signatures in association with the induction of the Yamanaka pluripotency factors and recruitment of JUN and BAF, which promote increases in histone activation marks and opening of chromatin. These and other findings described in this review have uncovered a pivotal role for MUC1-C in integrating lineage plasticity and epigenetic reprogramming, which are transient in wound repair and sustained in promoting CSC progression.

Addiction of Cancer Stem Cells to MUC1-C in Triple-Negative Breast Cancer Progression

“…In this regard, MUC1-C induces the Yamanaka pluripotency factors, EMT and self-renewal in pancreatic cancers [ 108 ] and castration-resistant prostate cancer (CRPC) [ 109 ]. In further support of the TNBC findings and consistent with driving the CSC state, MUC1-C also integrates lineage plasticity with chromatin remodeling, genotoxic drug resistance and immune evasion in these models [ 62 , 88 , 110 , 111 , 112 ].…”

“…Similar results were obtained for the EGR1 and LY6E stemness-associated genes, indicating that this MUC1-C-induced pathway of chromatin remodeling activates multiple genes that contribute to the TNBC CSC state. Taken together with regulation of the NuRD complex, these findings support an important role for MUC1-C in chromatin remodeling that drives luminal→basal dedifferentiation and lineage plasticity of TNBC CSCs [ 62 ].…”

“…MUC1 consists of two subunits that are formed by autoproteolysis of the translated protein Macao et al 2006 [ 59 ]: (i) an extracellular N -terminal subunit (MUC1-N) with the glycosylated TRs that are characteristic of the mucin family and (ii) a transmembrane C-terminal subunit (MUC1-C) [ 57 , 58 ]. The MUC1-N/MUC1-C heterodimeric complex is expressed at the apical borders of normal epithelial cells, where it functions in protection against damage and inflammation ( Figure 1 ) [ 57 , 58 , 60 , 61 , 62 ]. With loss of apical–basal polarity in response to disruption of homeostasis, MUC1-N is shed into a protective mucin barrier, where it forms complexes with pathogens that are then excreted by mucociliary transport.…”

“…In turn, galectin-3 acts as a bridge to facilitate the association of MUC1-C with EGFR, FGFR, HER2 and other RTKs, and to activate their downstream signaling pathways ( Figure 1 ) [ 63 , 64 , 65 , 66 , 67 ]. Activation of MUC1-C is associated with the formation of homodimers that are imported into the nucleus by importin-β and interactions with the nuclear pore complex [ 58 , 62 , 68 ]. In the nucleus, MUC1-C interacts directly with transcription factors, including STAT3 [ 69 ], WNT/β-catenin/TCF4 [ 70 ], NF-κB [ 71 ] and MYC [ 72 ], which as noted above have been linked to the CSC state, and contributes to the regulation of their target genes ( Figure 1 ) [ 58 , 61 ].…”

“…MUC1-C CD is an intrinsically disordered protein devoid of kinase activity that includes a CQCRRK motif, which is necessary for MUC1-C homodimerization and function as an oncoprotein [ 58 ]. In this way, the MUC1-C cytoplasmic domain is phosphorylated by multiple kinases, such as RTKs, SRC, ABL and GSK3β, that in turn regulate direct interactions between MUC1-C and downstream effectors, including the MYC, NF-κB, STAT3 and WNT/β-catenin/TCF4 TFs, linked to the CSC state ( Figure 3 ) [ 58 , 61 , 62 ].…”