Silencing of hHS6ST2 inhibits progression of pancreatic cancer through inhibition of Notch signalling

Biochem J. 2011 Jun 1;436(2):271-82. doi: 10.1042/BJ20110297.

Abstract

Many of the ligands involved in developmental processes require HS (heparan sulfate) to modulate signal transduction. hHS6ST2 (human heparan sulfate D-glucosaminyl 6-O-sulfotransferase-2) is a Golgi-resident enzyme that usually acts on GlcA/IdoA(2S)-GlcNAc/NS disaccharide-6-sulfate modifications within the HS sequence. Emerging evidence indicates the importance of 6-O-sulfation in a number of developmental processes. However, any correlation with cancer-related events remains largely unexplored. In the present study, we found that hHS6ST2, but not other variants, was activated in human PC (pancreatic cancer). shRNA (short hairpin RNA)-mediated silencing of endogenous hHS6ST2 expression in the PC cell line PANC-1 inhibited cell invasion and migration. hHS6ST2 knockdown also resulted in markedly reduced tumorigenesis in immunocompromised mice. To specifically explore the molecular alterations resulting from depletion of hHS6ST2-generated 6-O-sulfation, we employed two-dimensional gel electrophoresis technology followed by nano-HPLC-ESI (electrospray ionization)-tandem MS to separate and identify total proteins from PC cells. Our data suggest that hHS6ST2 potentiates Notch signalling in PC cells. We also identified a role for hHS6ST2 in the growth and tumorigenicity of these cells which, at least in part, acts through Notch-mediated EMT (epithelial-mesenchymal transition) and angiogenesis. The results of the present study suggest that hHS6ST2 could be an attractive target for PC therapy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Disease Progression*
  • Down-Regulation / genetics
  • Endothelial Cells / physiology
  • Female
  • Gene Knockdown Techniques / methods
  • Gene Silencing / physiology*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Receptors, Notch / antagonists & inhibitors*
  • Receptors, Notch / physiology
  • Signal Transduction / physiology*
  • Sulfotransferases / deficiency
  • Sulfotransferases / genetics*

Substances

  • Receptors, Notch
  • HS6ST2 protein, human
  • Sulfotransferases