Targeting UDP-α-D-glucose 6-dehydrogenase inhibits glioblastoma growth and migration

Oncogene. 2018 May;37(20):2615-2629. doi: 10.1038/s41388-018-0138-y. Epub 2018 Feb 26.

Abstract

UDP-glucose 6-dehydrogenase (UGDH) produces UDP-α-D-glucuronic acid, the precursors for glycosaminoglycans (GAGs) and proteoglycans of the extracellular matrix. Elevated GAG formation has been implicated in a variety of human diseases, including glioblastoma (GBM). In our previous study, we found that Krüppel-like factor 4 (KLF4) promotes GBM cell migration by binding to methylated DNA, mainly methylated CpGs (mCpG) and transactivating gene expression. We identified UDGH as one of the downstream targets of KLF4-mCpG binding activity. In this study, we show that KLF4 upregulates UGDH expression in a mCpG-dependent manner, and UGDH is required for KLF4-induced cell migration in vitro. UGDH knockdown decreases GAG abundance in GBM cells, as well as cell proliferation and migration in vitro. In intracranial xenografts, reduced UGDH inhibits tumor growth and migration, accompanied by a decrease in the expression of extracellular matrix proteins such as tenascin C, brevican. Our studies demonstrate a novel DNA methylation-dependent UGDH upregulation by KLF4. Developing UGDH antagonists to decrease the synthesis of extracellular matrix components will be a useful strategy for GBM therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / genetics
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • CpG Islands
  • DNA Methylation
  • Enzyme Inhibitors / pharmacology
  • Gene Knockdown Techniques
  • Glioblastoma / enzymology*
  • Glioblastoma / genetics
  • Glycosaminoglycans / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Neoplasm Transplantation
  • Proteoglycans / metabolism
  • Up-Regulation* / drug effects
  • Uridine Diphosphate Glucose Dehydrogenase / antagonists & inhibitors
  • Uridine Diphosphate Glucose Dehydrogenase / genetics*

Substances

  • Enzyme Inhibitors
  • GKLF protein
  • Glycosaminoglycans
  • Kruppel-Like Transcription Factors
  • Proteoglycans
  • Uridine Diphosphate Glucose Dehydrogenase