title: O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies.
abstract: The signal transducer and activator of transcription 5 (STAT5) regulates differentiation, survival, proliferation and transformation of hematopoietic cells. Upon cytokine stimulation, STAT5 tyrosine phosphorylation (pYSTAT5) is transient, while in diverse neoplastic cells persistent overexpression and enhanced pYSTAT5 are frequently found. Post-translational modifications might contribute to enhanced STAT5 activation in the context of transformation, but the strength and duration of pYSTAT5 are incompletely understood. We found that O-GlcNAcylation and tyrosine phosphorylation act together to trigger pYSTAT5 levels and oncogenic transcription in neoplastic cells. The expression of a mutated hyperactive gain-of-function (GOF) STAT5 without O-GlcNAcylation resulted in decreased tyrosine phosphorylation, oligomerization and transactivation potential and complete loss of oncogenic transformation capacity. The lack of O-GlcNAcylation diminished phospho-ERK and phospho-AKT levels. Our data show that O-GlcNAcylation of STAT5 is an important process that contributes to oncogenic transcription through enhanced STAT5 tyrosine phosphorylation and oligomerization driving myeloid transformation. O-GlcNAcylation of STAT5 could be required for nutrient sensing and metabolism of cancer cells.
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Department of Biomedical Science, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Freund
authors.affiliation: Department of Pharmacology, Boehringer Ingelheim RCV GmbH &Co KG, Vienna, Austria.
authors.forename: M A
authors.initials: MA
authors.lastname: Kerenyi
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Hager
authors.affiliation: Department of Biochemistry, Center for Molecular Biomedicine, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Department of Biomedical Science, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Wingelhofer
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Department of Biomedical Science, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: H T T
authors.initials: HTT
authors.lastname: Pham
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Department of Biomedical Science, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Elabd
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Key Laboratory of Human Disease Comparative Medicine, Ministry of Health; Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Internal Medicine I, Division Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Valent
authors.affiliation: CNRS UMR 7292, Université François Rabelais, Tours, France.
authors.forename: F
authors.initials: F
authors.lastname: Gouilleux
authors.affiliation: Department of Biomedical Science, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
authors.forename: V
authors.initials: V
authors.lastname: Sexl
authors.affiliation: Department of Toxicology, University Medical Center, Mainz, Germany.
authors.forename: O H
authors.initials: OH
authors.lastname: Krämer
authors.affiliation: Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Groner
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Department of Biomedical Science, Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.|Medical University of Vienna, Vienna, Austria.
authors.forename: R
authors.identifier: 0000-0003-0918-9463
authors.initials: R
authors.lastname: Moriggl
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006031:Glycosylation; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D008221:Lymphoid Tissue / Q000166:cytology; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000235:genetics; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D007377:Interleukin-3; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins; D019000:Phosphotyrosine; D013912:Threonine; D000117:Acetylglucosamine