Abnormally Glycosylated MUC1 Establishes a Positive Feedback Circuit of Inflammatory Cytokines, Mediated by NF-κB P65 and EzH2, in Colitis-associated Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Dec 30

PMID 29285251

Citations 9

Authors

Sandra Cascio

Jacque L Faylo

Joshua C Sciurba

Jia Xue

Sarangarajan Ranganathan

Jason J Lohmueller

Pamela L Beatty

Olivera J Finn

Affiliations

Soon will be listed here.

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 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.

Citing Articles

The multifaceted role of MUC1 in tumor therapy resistance.

Jin W, Zhang M, Dong C, Huang L, Luo Q Clin Exp Med. 2022; 23(5):1441-1474.

PMID: 36564679 DOI: 10.1007/s10238-022-00978-y.

Mucin-Type O-Glycans: Barrier, Microbiota, and Immune Anchors in Inflammatory Bowel Disease.

Zhang Y, Wang L, Ocansey D, Wang B, Wang L, Xu Z J Inflamm Res. 2021; 14:5939-5953.

PMID: 34803391 PMC: 8598207. DOI: 10.2147/JIR.S327609.

Mucin-Type O-GalNAc Glycosylation in Health and Disease.

Bagdonaite I, Pallesen E, Nielsen M, Bennett E, Wandall H Adv Exp Med Biol. 2021; 1325:25-60.

PMID: 34495529 DOI: 10.1007/978-3-030-70115-4_2.

Membrane-associated mucins of the human ocular surface in health and disease.

Martinez-Carrasco R, Argueso P, Fini M Ocul Surf. 2021; 21:313-330.

PMID: 33775913 PMC: 8328898. DOI: 10.1016/j.jtos.2021.03.003.

Inflammation-Induced Abnormal Expression of Self-molecules on Epithelial Cells: Targets for Tumor Immunoprevention.

Jacqueline C, Lee A, Frey N, Minden J, Finn O Cancer Immunol Res. 2020; 8(8):1027-1038.

PMID: 32467324 PMC: 7415557. DOI: 10.1158/2326-6066.CIR-19-0870.

References

Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso M . Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014; 2014:149185. PMC: 4036716. DOI: 10.1155/2014/149185. View

Tonini T, Bagella L, DAndrilli G, Claudio P, Giordano A . Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A. Oncogene. 2004; 23(28):4930-7. DOI: 10.1038/sj.onc.1207608. View

Feagins L, Souza R, Spechler S . Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer. Nat Rev Gastroenterol Hepatol. 2009; 6(5):297-305. DOI: 10.1038/nrgastro.2009.44. View

Lee S, Li Z, Wu Z, Aau M, Guan P, Karuturi R . Context-specific regulation of NF-κB target gene expression by EZH2 in breast cancers. Mol Cell. 2011; 43(5):798-810. DOI: 10.1016/j.molcel.2011.08.011. View

Tagde A, Rajabi H, Stroopinsky D, Gali R, Alam M, Bouillez A . MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia. Oncotarget. 2016; 7(26):38974-38987. PMC: 5129907. DOI: 10.18632/oncotarget.9777. View

Thomas C, Gustafsson J . The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer. 2011; 11(8):597-608. DOI: 10.1038/nrc3093. View

Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C . The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2005; 439(7078):871-4. DOI: 10.1038/nature04431. View

Liu X, Lin X, Gaffen S . Crucial role for nuclear factor of activated T cells in T cell receptor-mediated regulation of human interleukin-17. J Biol Chem. 2004; 279(50):52762-71. DOI: 10.1074/jbc.M405764200. View

Grivennikov S, Greten F, Karin M . Immunity, inflammation, and cancer. Cell. 2010; 140(6):883-99. PMC: 2866629. DOI: 10.1016/j.cell.2010.01.025. View

10.

Delmotte P, Degroote S, Merten M, Bernigaud A, Van Seuningen I, FIGARELLA C . Influence of culture conditions on the alpha 1,2-fucosyltransferase and MUC gene expression of a transformed cell line MM-39 derived from human tracheal gland cells. Biochimie. 2001; 83(8):749-55. DOI: 10.1016/s0300-9084(01)01320-7. View

11.

Shi B, Liang J, Yang X, Wang Y, Zhao Y, Wu H . Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol. 2007; 27(14):5105-19. PMC: 1951944. DOI: 10.1128/MCB.00162-07. View

12.

Kovarik A, Peat N, Wilson D, Gendler S, Taylor-Papadimitriou J . Analysis of the tissue-specific promoter of the MUC1 gene. J Biol Chem. 1993; 268(13):9917-26. View

13.

Kadayakkara D, Beatty P, Turner M, Janjic J, Ahrens E, Finn O . Inflammation driven by overexpression of the hypoglycosylated abnormal mucin 1 (MUC1) links inflammatory bowel disease and pancreatitis. Pancreas. 2010; 39(4):510-5. PMC: 2859977. DOI: 10.1097/MPA.0b013e3181bd6501. View

14.

Abe M, Kufe D . Characterization of cis-acting elements regulating transcription of the human DF3 breast carcinoma-associated antigen (MUC1) gene. Proc Natl Acad Sci U S A. 1993; 90(1):282-6. PMC: 45644. DOI: 10.1073/pnas.90.1.282. View

15.

Li X, Gonzalez M, Toy K, Filzen T, Merajver S, Kleer C . Targeted overexpression of EZH2 in the mammary gland disrupts ductal morphogenesis and causes epithelial hyperplasia. Am J Pathol. 2009; 175(3):1246-54. PMC: 2731143. DOI: 10.2353/ajpath.2009.090042. View

16.

Fussbroich B, Wagener N, Macher-Goeppinger S, Benner A, Falth M, Sultmann H . EZH2 depletion blocks the proliferation of colon cancer cells. PLoS One. 2011; 6(7):e21651. PMC: 3135584. DOI: 10.1371/journal.pone.0021651. View

17.

MURPHY T, Cleveland M, Kulesza P, Magram J, Murphy K . Regulation of interleukin 12 p40 expression through an NF-kappa B half-site. Mol Cell Biol. 1995; 15(10):5258-67. PMC: 230773. DOI: 10.1128/MCB.15.10.5258. View

18.

Terzic J, Grivennikov S, Karin E, Karin M . Inflammation and colon cancer. Gastroenterology. 2010; 138(6):2101-2114.e5. DOI: 10.1053/j.gastro.2010.01.058. View

19.

Beatty P, Narayanan S, Gariepy J, Ranganathan S, Finn O . Vaccine against MUC1 antigen expressed in inflammatory bowel disease and cancer lessens colonic inflammation and prevents progression to colitis-associated colon cancer. Cancer Prev Res (Phila). 2010; 3(4):438-46. PMC: 2853738. DOI: 10.1158/1940-6207.CAPR-09-0194. View

20.

Ahmad R, Raina D, Joshi M, Kawano T, Ren J, Kharbanda S . MUC1-C oncoprotein functions as a direct activator of the nuclear factor-kappaB p65 transcription factor. Cancer Res. 2009; 69(17):7013-21. PMC: 2760979. DOI: 10.1158/0008-5472.CAN-09-0523. View