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 (HBP).
Increased flux through the HBP leads to increases in the post-translation addition of O-linked-β-N-acetylglucosamine (O-GlcNAc) 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 O-GlcNAc transferase (OGT) is overexpressed in prostate cancer compared to normal prostate epithelium, and OGT protein and O-GlcNAc levels are elevated in prostate carcinoma cell lines. Reducing O-GlcNAcylation in PC3-ML cells was associated with reduced expression of matrix metalloproteinase-2 (MMP-2), MMP-9, and vascular endothelial growth factor (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 VEGF expression. Using a mouse model of metastasis, we found reduction of OGT expression blocked bone metastasis. Altogether, these data suggest that, as prostate cancer cells alter glucose and glutamine levels, O-GlcNAc 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.
Written by:
Lynch TP, Ferrer CM, Jackson SR, Shahriari KS, Vosseller K, Reginato MJ. Are you the author?
Drexel University College of Medicine, United States.
Reference: J Biol Chem. 2012 Jan 24. [Epub ahead of print]
PubMed Abstract
PMID: 22275356
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