Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1.

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 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.

• Authors: S A Caldwell, S R Jackson, K S Shahriari, T P Lynch, G Sethi, S Walker, K Vosseller, M J Reginato
• Journal: Oncogene (Oncogene) Vol. 29 Issue 19 Pg. 2831-42 (May 13 2010) ISSN: 1476-5594 [Electronic] England
• PMID: 20190804 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Enzyme Inhibitors
• FOXM1 protein, human
• Forkhead Box Protein M1
• Forkhead Transcription Factors
• Oncogene Proteins
• Cyclin-Dependent Kinase Inhibitor p27
• N-Acetylglucosaminyltransferases
• O-GlcNAc transferase
• Matrix Metalloproteinase 2
• Acetylglucosamine

Topics

• Acetylglucosamine (metabolism)
• Animals
• Base Sequence
• Breast Neoplasms (enzymology, genetics, metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic (drug effects)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Enzyme Inhibitors (pharmacology)
• Female
• Forkhead Box Protein M1
• Forkhead Transcription Factors (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Humans
• Matrix Metalloproteinase 2 (genetics, metabolism)
• Mice
• N-Acetylglucosaminyltransferases (antagonists & inhibitors, deficiency, genetics, metabolism)
• Neoplasm Invasiveness (pathology)
• Oncogene Proteins (metabolism)
• Phenotype
• Up-Regulation (drug effects)