Overexpression of GalNAc-transferase GalNAc-T3 promotes pancreatic cancer cell growth

K. Taniuchi, R. L. Cerny, A. Tanouchi, K. Kohno, N. Kotani, K. Honke, T. Saibara, M. A. Hollingsworth

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4843-4854
Number of pages12
JournalOncogene
Volume30
Issue number49
DOIs
StatePublished - Dec 8 2011

Keywords

  • GalNAc-T3pancreatic cancer
  • O-glycosylation
  • apoptosis
  • cell growth
  • polypeptide N-acetylgalactosaminyl-transferase

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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