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

• DOI: 10.1016/j.ccell.2016.06.023
• Publication Date: 2016-08-08T17:52:27Z
• Authors: Stefan Burén; Ana L. Gomes; Ana Teijeiro; Mohamad-Ali Fawal; Mahmut Yilmaz; Krishna S. Tummala; Manuel Perez; Manuel Rodriguez-...; Ramón Campos-Olivas; Diego Megías; Nabil Djouder
• Keywords: 0303 health sciences; Liver Neoplasms; Intracellular Signaling Peptides and Proteins; Glucose Tolerance Test; N-Acetylglucosaminyltransferases; Transfection; Proto-Oncogene Proteins c-myc; Repressor Proteins; Mice; 03 medical and health sciences; Glucose; HEK293 Cells; Animals; Humans; RNA, Small Interfering; HeLa Cells

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.