Cancer cells upregulate glycolysis, increasing glucose uptake to meet energy needs. A small fraction of a cell's glucose enters the hexosamine biosynthetic pathway (HBP), which regulates levels of O−linked beta−N−acetylglucosamine (O−GlcNAc), a carbohydrate posttranslational modification of diverse nuclear and cytosolic proteins. We discovered that breast cancer cells upregulate the HBP, including increased O−GlcNAcation and elevated expression of O−GlcNAc transferase (OGT), which is the enzyme catalyzing the addition of O−GlcNAc to proteins. Reduction of O−GlcNAcation through RNA interference of OGT in breast cancer cells leads to inhibition of tumor growth both in vitro and in vivo and is associated with decreased cell−cycle progression and increased expression of the cell−cycle inhibitor p27(Kip1). Elevation of p27(Kip1) was associated with decreased expression and activity of the oncogenic transcription factor FoxM1, a known regulator of p27(Kip1) stability through transcriptional control of Skp2. Reducing O−GlcNAc levels in breast cancer cells decreased levels of FoxM1 protein and caused a decrease in multiple FoxM1−specific targets, including Skp2. Moreover, reducing O−GlcNAcation decreased cancer cell invasion and was associated with the downregulation of matrix metalloproteinase−2, a known FoxM1 target. Finally, 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.Oncogene advance online publication, 1 March 2010; doi:10.1038/onc.2010.41.

PMID: 20190804 [PubMed − as supplied by publisher] Source: National Library of Medicine.