title: Regulation of OGT by URI in Response to Glucose Confers c-MYC-Dependent Survival Mechanisms.
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.
authors: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors: Stefan
authors: S
authors: Burén
authors: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors: Ana L
authors: AL
authors: Gomes
authors: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors: Ana
authors: A
authors: Teijeiro
authors: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors: Mohamad-Ali
authors: MA
authors: Fawal
authors: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors: Mahmut
authors: M
authors: Yilmaz
authors: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors: Krishna S
authors: KS
authors: Tummala
authors: Biotechnology Programme, Confocal Microscopy Core Unit, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors: Manuel
authors: M
authors: Perez
authors: Department of Research Pathology, Cancer Institute, University College London, London WC1E 6JJ, UK.
authors: Manuel
authors: M
authors: Rodriguez-Justo
authors: Structural Biology and Biocomputing Programme, Spectroscopy and Nuclear Magnetic Resonance Unit, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors: Ramón
authors: R
authors: Campos-Olivas
authors: Biotechnology Programme, Confocal Microscopy Core Unit, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors: Diego
authors: D
authors: Megías
authors: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain. Electronic address: ndjouder@cnio.es.
authors: Nabil
authors: N
authors: Djouder
mesh_terms: D000818:Animals; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D014162:Transfection
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C117184:URI1 protein, human; D017351:N-Acetylglucosaminyltransferases; D005947:Glucose