We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1.
- Authors
Caldwell, S. A.; Jackson, S. R.; Shahriari, K. S.; Lynch, T. P.; Sethi, G.; Walker, S.; Vosseller, K.; Reginato, M. J.
- Abstract
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 β-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 p27Kip1. Elevation of p27Kip1 was associated with decreased expression and activity of the oncogenic transcription factor FoxM1, a known regulator of p27Kip1 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.
- Subjects
BREAST cancer treatment; CARCINOGENESIS; CANCER cell growth; TUMOR growth prevention; TRANSFERASES; TRANSCRIPTION factors; PREVENTION
- Publication
Oncogene, 2010, Vol 29, Issue 19, p2831
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2010.41