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Thesis
Role of ACSS2-Ser267 phosphorylation in glioblastoma cells
Master of Science (M.S.), Drexel University
Jun 2019
DOI:
https://doi.org/10.17918/0wx3-yc86
Abstract
Glioblastoma (GBM) is the most common malignant brain cancer and preferentially generate acetyl-CoA from acetate as an alternative fuel source to promote biosynthesis and tumorigenesis. Acetate is converted into acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2). The expression of ACSS2 is highly elevated in GBM cells and is required for GBM growth. We have discovered that O-GlcNAcylation regulates acetatedependent acetyl-CoA production by regulating phosphorylation of ACSS2 on Serine 267 by the cyclin dependent kinase 5 (CDK5). However, the functional role of phosphorylation of ACSS2 on Serine 267 is unclear. Here, we report that the phosphorylation on Ser-267 blocks degradation of ACSS2. Consistently, we show that the protein half-life of ACSS2 S267A mutant is significantly reduced compared to wildtype ACSS2 or ACSS2 S267D phospho-mimetic mutant. Additionally, we identify F-Box Only Protein 7 (FBXO7) as a potential E3 ubiquitin ligase for ACSS2 and show that genetic suppression of FBXO7 in GBM cells increases ACSS2 protein levels and promotes glioblastoma anchorage-independent growth. Thus, our results demonstrate that O-GlcNAcylation can regulate the phosphorylation of ACSS2 on Ser267 which is critical ACSS2 protein stability and GBM cell growth. Overall, we provide evidence that targeting OGT and ACSS2-S267 phosphorylation may have promising effects in the treatment of glioblastoma.
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Details
- Title
- Role of ACSS2-Ser267 phosphorylation in glioblastoma cells
- Creators
- Jing Ju - DU
- Contributors
- Jane Clifford (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 28 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 9512; 991014632313304721