Targeting Protein O-GlcNAc Modifications In Breast Cancer

摘要

Cancer cells upregulate glycolysis, increasing glucose uptake to meet energy needs. Approximately 2-5% of a cell's glucose enters the hexosamine biosynthetic pathway (HBP) which regulates levels of O-linked beta-N- acetylglucosamine (O-GlcNAc), a carbohydrate post-translational modification of diverse nuclear and cytosolic proteins. We have discovered that breast cancer cells upregulate the HBP, including increased O-GlcNAcation and elevated expression of O-GlcNAc transferase (OGT), the enzyme catalyzing addition of O- GlcNAc to proteins. Reduction of O-GlcNAcation via RNAi of OGT in breast cancer cells leads to inhibition of tumor growth in vitro as well as in vivo and associated with decreased cell cycle progression and increased expression of the cell cycle inhibitor p27(exp Kip1). Elevation of p27(exp Kip1) was associated with decreased expression and activity of the oncogenic transcription factor FoxM1 a known regulator of p27(exp Kip1) stability via transcriptional control of Skp2. Reducing O-GlcNAc levels in breast cancer cells decreased levels of FoxM1 protein and caused decrease in multiple FoxM1- specific targets including Skp2. Moreover, reducing O-GlcNAcation decreased cancer cell invasion and was associated with downregulation of MMP-2, a known FoxM1 target. Lastly, pharmacological inhibition of OGT in breast cancer cells had similar anti-growth and anti-invasion effects. These findings identify O- GlcNAc as a novel mechanism through which alterations in glucose metabolism regulate cancer growth and invasion and suggest that OGT may represent novel therapeutic targets for breast cancer.