Elevated O-GlcNAcylation is associated with disease states such as diabetes and cancer. O-GlcNAc transferase (OGT) is elevated in multiple cancers and inhibition of this enzyme genetically or pharmacologically inhibits oncogenesis. Here we show that O-GlcNAcylation modulates lipid metabolism in cancer cells. OGT regulates expression of the master lipid regulator the transcription factor sterol regulatory element binding protein 1 (SREBP-1) and its transcriptional targets both in cancer and lipogenic tissue. OGT regulates SREBP-1 protein expression via AMP Activated protein kinase (AMPK). SREBP-1 is critical for OGT-mediated regulation of cell survival and of lipid synthesis, as overexpression of SREBP-1 rescues lipogenic defects associated with OGT suppression, and tumor growth in vitro and in vivo. These results unravel a previously unidentified link between O-GlcNAcylation, lipid metabolism and the regulation of SREBP-1 in cancer and suggests a crucial role for O-GlcNAc signaling in transducing nutritional state to regulate lipid metabolism.

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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.

Venous malformations (VM) are slow-flow vascular lesions that result from morphogenesis errors. Composed of dysfunctional veins lacking smooth muscle cells, VMs grow slowly and may initially be managed by observation. Treatment is indicated for lesions that cause functional impairment. One treatment option is laser therapy, which is very effective due to its tissue penetration and relative selectivity. The Nd:YAG laser has been shown to treat small and moderately sized mucosal vascular lesions; in this case, it was applied in a staged approach for treatment of a massive venous malformation of the tongue. A 66-year-old male presented with a venous malformation involving the tongue and lower lip, the lesion estimated to be 10 x 14 x 15 cm in size. The Nd:YAG laser was used in three separate stages to photocoagulate the venous lesion. Follow-up for recurrence is ongoing, but currently shows complete malformation ablation with a 36.2% volume reduction after treatment. The Nd:YAG laser is an effective tool in the treatment of large vascular lesions. Successful laser application in a staged approach for the treatment of a venous malformation of this size and complexity further supports its clinical value. Monitoring for possible recurrence of the venous malformation should be ongoing.