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Accepted (AM)Open Access (License Unspecified), Open
Journal article
O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation
Oncogene, v 41(14), pp 2122-2136
Apr 2022
PMID: 35190642
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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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Details
- Title
- O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation
- Creators
- Lorela Ciraku - Drexel UniversityZachary A Bacigalupa - Drexel UniversityJing Ju - Drexel UniversityRebecca A Moeller - Drexel UniversityGiang Le Minh - Drexel UniversityRusia H Lee - Drexel UniversityMichael D Smith - Drexel UniversityChristina M Ferrer - Drexel UniversitySophie Trefely - Temple UniversityLuke T Izzo - Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.Mary T Doan - Temple UniversityWiktoria A Gocal - Drexel UniversityLuca D'Agostino - Drexel UniversityWenyin Shi - Thomas Jefferson UniversityJoshua G Jackson - Drexel UniversityChristos D Katsetos - Drexel UniversityKathryn E Wellen - Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.Nathaniel W Snyder - Temple UniversityMauricio J Reginato - Drexel University
- Publication Details
- Oncogene, v 41(14), pp 2122-2136
- Publisher
- Springer Nature
- Grant note
- R01 CA228339 / NCI NIH HHS T32 CA115299 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Pharmacology and Physiology; [Retired Faculty]; Hematology and Oncology; A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000758961200001
- Scopus ID
- 2-s2.0-85125228433
- Other Identifier
- 991019168303004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Genetics & Heredity
- Oncology