MUC1-C drives DNA methylation in cancer

publications have reported a previously unrecognized role for the MUC1-C oncoprotein in regulating DNA methyltransferase (DNMT) expression and thereby DNA methylation in human cancer cells [1, 2]. The MUC1-C transmembrane protein is aberrantly overexpressed in diverse human cancers and in certain hematologic malignancies, including acute myelo-genous leukemia (AML) [3]. Dysregulation of DNMTs and disruption of DNA methylation patterns are established hallmarks of the cancer cell [4]. MUC1-C has been linked to other hallmarks, such as (i) induction of the epithelial-mesenchymal transition (EMT), (ii) repression of tumor suppressor genes, (iii) activation of the MYC gene, and (iv) promotion of self-renewal capacity [3, 5]. However, there had been no known relationship between MUC1-C-induced signaling and the regulation of DNMTs and DNA methylation in cancer. DNMTs catalyze the transfer of a methyl group to cytosine in CpG dinucleotides [4]. DNMT1, which localizes at foci of DNA replication, is largely responsible for maintaining global and gene-specific CpG methylation. In addition, DNMT3a and DNMT3b typically contribute to de novo postreplicative DNA methylation patterns. DNA methylation in promoter regions is associated with transcriptional repression; whereas, DNA methylation in gene bodies can induce increases in transcription and alternative splicing [4]. In this respect, dysregulation of DNMTs in cancer cells can affect global programs of gene repression and activation. Despite this complexity, a notable finding is that both DNMT1 and DNMT3b are required for silencing genes in cancer cells [6]. The MUC1-C cytoplasmic domain is a 72-amino acid intrinsically disordered protein, a finding consistent with other oncogenic molecules that have the plasticity to direct the activation of multiple signaling pathways. Along these lines, the MUC1-C cytoplasmic domain interacts with diverse kinases and effectors that are linked to transformation [3, 5]. For instance, the MUC1-C cytoplasmic activates the WNT pathway by binding directly to β-catenin and promoting the activation of WNT target genes, such as CCND1 and MYC. MUC1-C also activates the inflammatory IKK€NF-κB pathway and drives the expression of NF-κB p65 target genes, including MUC1 itself in an auto-Editorial inductive loop. In addition, the MUC1-C€NF-κB p65 pathway induces the ZEB1 tumor suppressor gene and promotes ZEB1-mediated repression of genes encoding (i) factors, such as Crumbs 3 (CRB3), required for maintaining apical-basal polarity, (ii) miR-200c, an inducer of epithelial differentiation, and (iii) E-cadherin, a keystone of the adherens junction complex; all of which contribute to the EMT phenotype (Fig. 1) [7]. In concert with driving EMT, recent work has …