Overexpression of GalNAc-transferase GalNAc-T3 Promotes Pancreatic Cancer Cell Growth

Authors

Keisuke Taniuchi, University of Nebraska Medical Center
Ronald Cerny, University of Nebraska - LincolnFollow
Aki Tanouchi, Kochi University Medical School
Kimitoshi Kohno, University of Occupational and Environmental Health School of Medicine
Norihiro Kotani, Kochi University Medical School
Koichi Honke, Kochi University Medical School
Toshiji Saibara, Kochi University Medical School
Michael A. Hollingsworth, University of Nebraska Medical Center

Date of this Version

2011

Citation

Oncogene. 2011 December 8; 30(49): 4843–4854.

Comments

Copyright 2011 Macmillan Publishers Limited

Abstract

O-linked glycans of secreted and membrane bound proteins play an important role in the pathogenesis of pancreatic cancer by modulating immune responses, inflammation, and tumorigenesis. A critical aspect of O-glycosylation, the position at which proteins are glycosylated with N-acetyl-galactosamine on serine and threonine residues, is regulated by the substrate specificity of UDP-GalNAc: polypeptide N-acetylgalactosaminyl-transferases (GalNAc-Ts). Thus, GalNAc-Ts regulate the first committed step in O-glycosylated protein biosynthesis, determine sites of O-glycosylation on proteins, and are important for understanding normal and carcinoma-associated O-glycosylation. We have found that one of these enzymes, GalNAc-T3, is overexpressed in human pancreatic cancer tissues, and suppression of GalNAc-T3 significantly attenuates growth of pancreatic cancer cells in vitro and in vivo. In addition, suppression of GalNAc-T3 induces apoptosis of pancreatic cancer cells. Our results indicate that GalNAc-T3 is likely to be involved in pancreatic carcinogenesis. Modification of cellular glycosylation occurs in nearly all types of cancer as a result of alterations in the expression levels of glycosyltransferases. We report guanine nucleotide binding protein, alpha transducing activity polypeptide 1 (GNAT1) as a possible substrate protein of GalNAc-T3. GalNAc-T3 is associated with O-glycosylation of GNAT1, and affects the subcellular distribution of GNAT1. Knocking down endogenous GNAT1 significantly suppresses the growth/survival of PDAC cells. Our results imply that GalNAc-T3 contributes to the function of O-glycosylated proteins and thereby affects the growth and survival of pancreatic cancer cells. Thus, substrate proteins of GalNAc-T3 should serve as important therapeutic targets for pancreatic cancers.