Α1, 4‐Linked N‐acetylglucosamine suppresses gastric cancer development by inhibiting Mucin‐1‐mediated signaling. Issue 11 (31st August 2022)

• Record Type: Journal Article
• Authors: Fujii, Chifumi; Harumiya, Satoru; Sato, Yoshiko; Kawakubo, Masatomo; Matoba, Hisanori; Nakayama, Jun
• Is Part Of: Cancer science. Volume 113:Issue 11(2022)
• Page Start: 3852
• Page End: 3863
• Publication Date: 2022-08-31
• Subjects: differentiated‐type gastric cancer -- invasion -- malignant phenotype -- tumor suppressor -- αGlcNAc‐binding protein; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.15530
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Gastric cancer is the second leading cause of cancer deaths worldwide, and more understanding of its molecular basis is urgently needed. Gastric gland mucin secreted from pyloric gland cells, mucous neck cells, and cardiac gland cells of the gastric mucosa harbors unique O ‐glycans carrying terminal α1, 4‐linked N ‐acetylglucosamine (αGlcNAc) residues. We previously reported that αGlcNAc loss correlated positively with poor outcomes for patients with differentiated‐type gastric cancer. However, the molecular mechanisms underlying these outcomes remained poorly understood. Here, we examined the effects of upregulated αGlcNAc expression on malignant phenotypes of the differentiated‐type gastric cancer cell lines, AGS and MKN7. Upregulation of αGlcNAc following ectopic expression of its biosynthetic enzyme attenuated cell proliferation, motility, and invasiveness of AGS and MKN7 cells in vitro. Moreover, AGS cell tumorigenicity was significantly suppressed by αGlcNAc overexpression in a xenograft model. To define the molecular mechanisms underlying these phenotypes, we investigated αGlcNAc binding proteins in AGS cells and identified Mucin‐1 (MUC1) and podocalyxin. Both proteins were colocalized with αGlcNAc on human gastric cancer cells. We also found that αGlcNAc was bound to MUC1 in murine normal gastric mucosa. When we assessed the effects of αGlcNAc binding to MUC1, we found that αGlcNAc blocked galectin‐3 binding to MUC1, phosphorylation of the MUC1 C‐terminus, and recruitment of Src and β‐catenin to that C‐terminus. These results suggest that αGlcNAc regulates cancer cell phenotypes by dampening MUC1 signal transduction. Abstract : We previously reported that A4gnt, which encodes α4GnT, deficient mice completely lost αGlcNAc, and spontaneously developed differentiated‐type adenocarcinoma. Furthermore, loss of αGlcNAc correlated with poor outcome of differentiated‐type gastric cancer patients. However, the molecular mechanisms why loss of αGlcNAc leads to gastric cancer development are poorly understood. In this study, we demonstrate that malignant phenotypes are attenuated by forced expression of αGlcNAc in 2 differentiated‐type gastric cancer cell lines. We also show that αGlcNAc acts as a tumor suppressor by binding to MUC1, decreasing MUC1 signaling.