Role of O-GlcNAc transferase in cancer cell metastasis and metabolism

Thomas P. Lynch

doi:10.17918/00008340

Cancer cells universally increase glucose and glutamine consumption leading to the altered metabolic state known as the Warburg effect; one metabolic pathway, highly dependent on glucose and glutamine, is the hexosamine biosynthetic pathway. Increased flux through the hexosamine biosynthetic pathway leads to increases in the post-translation addition of O-G1cNAc on various nuclear and cytosolic proteins. A number of these target proteins are implicated in cancer and, recently, O-GlcNAcylation was shown to play a role in breast cancer; however, O-GlcNAcylation in other cancers remains poorly defined. Here, we show OGT is overexpressed in prostate cancer compared to normal prostate epithelium, and OGT protein and O-GIcNAc levels are elevated in prostate carcinoma cell lines. Reducing O-GlcNAcylation in PC3-ML cells was associated with reduced expression MMP-2, MMP-9, and VEGF, resulting in inhibition of invasion and angiogenesis. OGT-mediated regulation of invasion and angiogenesis was dependent upon regulation of the oncogenic transcription factor FoxM1, a key regulator of invasion and angiogenesis, as reducing OGT expression led to increased FoxM1 protein degradation. Conversely, overexpression of a FoxM1 degradation-resistant mutant abrogated OGT RNAi-mediated effects on invasion, MMP levels, angiogenesis, and xiv VEGF expression. Using a mouse model of metastasis, we found reduction of OGT expression blocked bone metastasis. In addition to the regulation of metastasis, we show that OGT is a central factor for the glycolytic shift seen in cancer cells. RNAi-mediated knockdown and pharmacological inhibition of OGT leads to impaired glucose uptake, lactate production, and decreased ATP levels in cancer cells. We demonstrate that reducing OGT levels leads to decreased levels of HIF-1 protein and transcriptional targets, including GLUT1. This decrease in HIF-1 levels results in metabolic stress leading to increased LKB1 and AMPK activation and mTOR inhibition. Regulation of HIF-1 and GLUT1 is critical for OGT-mediated inhibition of growth and glycolysis, as overexpression of stable HIF-1 mutant rescues metabolic defects and growth in OGT-depleted cancer cells. Taken together, these data indicate, for the first time, that flux through HBP, via O- GlcNAcylation, connects with key nutrient sensing pathways regulating cancer metabolism through, in part, regulating a key metabolic regulator HIF-1. Altogether, these data suggest that, as cancer cells alter glucose and glutamine levels, O-GIcNAc modifications and OGT levels become elevated and are required for regulation of malignant properties, implicating OGT as a novel therapeutic target in the treatment of cancer.

Role of O-GlcNAc transferase in cancer cell metastasis and metabolism

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Role of O-GlcNAc transferase in cancer cell metastasis and metabolism

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