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O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation.
Ciraku, Lorela; Bacigalupa, Zachary A; Ju, Jing; Moeller, Rebecca A; Le Minh, Giang; Lee, Rusia H; Smith, Michael D; Ferrer, Christina M; Trefely, Sophie; Izzo, Luke T; Doan, Mary T; Gocal, Wiktoria A; D'Agostino, Luca; Shi, Wenyin; Jackson, Joshua G; Katsetos, Christos D; Wellen, Kathryn E; Snyder, Nathaniel W; Reginato, Mauricio J.
Afiliación
  • Ciraku L; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • Bacigalupa ZA; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • Ju J; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • Moeller RA; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • Le Minh G; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • Lee RH; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • Smith MD; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • Ferrer CM; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • Trefely S; Center for Metabolic Disease Research, Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA.
  • Izzo LT; Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Doan MT; Center for Metabolic Disease Research, Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA.
  • Gocal WA; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • D'Agostino L; Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • Shi W; Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • Jackson JG; Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • Katsetos CD; Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
  • Wellen KE; Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Snyder NW; Center for Metabolic Disease Research, Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA.
  • Reginato MJ; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA. mjr53@drexel.edu.
Oncogene ; 41(14): 2122-2136, 2022 04.
Article en En | MEDLINE | ID: mdl-35190642
Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-CoA and lipid production by regulating phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5). OGT is required and sufficient for GBM cell growth and regulates acetate conversion to acetyl-CoA and lipids. Elevating O-GlcNAcylation in GBM cells increases phosphorylation of ACSS2 on Ser-267 in a CDK5-dependent manner. Importantly, we show that ACSS2 Ser-267 phosphorylation regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Importantly, we show that pharmacologically targeting OGT and CDK5 reduces GBM growth ex vivo. Thus, the OGT/CDK5/ACSS2 pathway may be a way to target altered metabolic dependencies in brain tumors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glioblastoma Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glioblastoma Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido