Oncotarget

Research Papers:

Abnormally glycosylated MUC1 establishes a positive feedback circuit of inflammatory cytokines, mediated by NF-κB p65 and EzH2, in colitis-associated cancer

Sandra Cascio _, Jacque L. Faylo, Joshua C. Sciurba, Jia Xue, Sarangarajan Ranganathan, Jason J. Lohmueller, Pamela L. Beatty and Olivera J. Finn

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Oncotarget. 2017; 8:105284-105298. https://doi.org/10.18632/oncotarget.22168

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Abstract

Sandra Cascio1,2, Jacque L. Faylo3, Joshua C. Sciurba1, Jia Xue1, Sarangarajan Ranganathan4, Jason J. Lohmueller1, Pamela L. Beatty1 and Olivera J. Finn1

1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA

2Fondazione Ri.Med, Palermo, 90133, Italy

3Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA

4Division of Pediatric Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA

Correspondence to:

Sandra Cascio, email: sac131@pitt.edu

Keywords: colitis-associated cancer; Mucin 1; altered glycosylation; EzH2; pro-inflammatory cytokines

Received: June 14, 2017     Accepted: September 08, 2017     Published: October 27, 2017

ABSTRACT

The abnormal hypoglycosylated form of the epithelial mucin MUC1 is over-expressed in chronic inflammation and on human adenocarcinomas, suggesting its potential role in inflammation-driven tumorigenesis. The presence of human MUC1 aggravates colonic inflammation and increases tumor initiation and progression in an in vivo AOM/DSS mouse model of colitis-associated cancer (CAC). High expression levels of pro-inflammatory cytokines, including TNF-α and IL-6, were found in MUC1+ inflamed colon tissues. Exogenous TNF-α promoted the transcriptional activity of MUC1 as well as over-expression of its hypoglycosylated form in intestinal epithelial cells (IECs). In turn, hypoglycosylated MUC1 in IECs associated with p65 and up-regulated the expression of NF-κB-target genes encoding pro-inflammatory cytokines. Intestinal chronic inflammation also increased the expression of histone methyltransferase Enhancer of Zeste protein-2 (EzH2) and its interaction with cytokine promoters. Consequently, EzH2 was a positive regulator of MUC1 and p65-mediated IL-6 and TNF-α gene expression, and this function was not dependent on its canonical histone H3K27 methyltransferase activity. Our findings provide a mechanistic basis for already known tumorigenic role of the hypoglycosylated MUC1 in CAC, involving a transcriptional positive feedback loop of pro-inflammatory cytokines.


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