Regulation of OGT by URI in Response to Glucose Confers c-MYC-Dependent Survival Mechanisms

Cancer Cell. 2016 Aug 8;30(2):290-307. doi: 10.1016/j.ccell.2016.06.023.

Abstract

Cancer cells can adapt and survive under low nutrient conditions, but underlying mechanisms remain poorly explored. We demonstrate here that glucose maintains a functional complex between the co-chaperone URI, PP1γ, and OGT, the enzyme catalyzing O-GlcNAcylation. Glucose deprivation induces the activation of PKA, which phosphorylates URI at Ser-371, resulting in PP1γ release and URI-mediated OGT inhibition. Low OGT activity reduces O-GlcNAcylation and promotes c-MYC degradation to maintain cell survival. In the presence of glucose, PP1γ-bound URI increases OGT and c-MYC levels. Accordingly, mice expressing non-phosphorylatable URI (S371A) in hepatocytes exhibit high OGT activity and c-MYC stabilization, accelerating liver tumorigenesis in agreement with c-MYC oncogenic functions. Our work uncovers that URI-regulated OGT confers c-MYC-dependent survival functions in response to glucose fluctuations.

MeSH terms

  • Animals
  • Glucose / administration & dosage
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Mice
  • N-Acetylglucosaminyltransferases / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Repressor Proteins
  • Transfection

Substances

  • Intracellular Signaling Peptides and Proteins
  • MYC protein, human
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Repressor Proteins
  • URI1 protein, human
  • N-Acetylglucosaminyltransferases
  • Glucose