title: Overexpression of GalNAc-transferase GalNAc-T3 promotes pancreatic cancer cell growth.
abstract: O-linked glycans of secreted and membrane-bound proteins have 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 the 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 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 the nucleotide-binding protein, α-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.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. jm-ktaniuchi@kochi-u.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Taniuchi
authors.forename: R L
authors.initials: RL
authors.lastname: Cerny
authors.forename: A
authors.initials: A
authors.lastname: Tanouchi
authors.forename: K
authors.initials: K
authors.lastname: Kohno
authors.forename: N
authors.initials: N
authors.lastname: Kotani
authors.forename: K
authors.initials: K
authors.lastname: Honke
authors.forename: T
authors.initials: T
authors.lastname: Saibara
authors.forename: M A
authors.initials: MA
authors.lastname: Hollingsworth
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006031:Glycosylation; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D017350:N-Acetylgalactosaminyltransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D034622:RNA Interference; D013379:Substrate Specificity; D015293:Transducin; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D020962:Heterotrimeric GTP-Binding Proteins; D017350:N-Acetylgalactosaminyltransferases; D015293:Transducin; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C034809:GNAT1 protein, human