Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation 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 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. 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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The categories of this paper are: epidemiology
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The categories of this paper are: immunology
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The categories of this paper are: cell
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The categories of this paper are: scientific
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The categories of this paper are: developmental
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The categories of this paper are: biophysics
7
The categories of this paper are: ecology
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The categories of this paper are: genetics
9
The categories of this paper are: synthetic
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The categories of this paper are: animal
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The categories of this paper are: pathology
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The categories of this paper are: toxicology
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The categories of this paper are: zoology
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The categories of this paper are: and
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The categories of this paper are: communication
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The categories of this paper are: molecular