Journal Article

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

Jackson, S R, Sethi, G, Reginato, M J, Walker, S, Shahriari, K S, Vosseller, K, Caldwell, S A, Lynch, T P

2010

Overview

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 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/80/86/2369 / 692/420/755 / 692/699/67/1347 / Acetylglucosamine - metabolism / Animals / Apoptosis / Base Sequence / Biological and medical sciences / Breast cancer / Breast Neoplasms - enzymology / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Care and treatment / Cell Biology / Cell cycle / Cell Cycle - drug effects / Cell Line, Tumor / Cell physiology / Cell Proliferation - drug effects / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Cell Transformation, Neoplastic - drug effects / Control / Cyclin-dependent kinase inhibitor p27 / Cyclin-Dependent Kinase Inhibitor p27 - metabolism / Enzyme Inhibitors - pharmacology / Female / Forkhead Box Protein M1 / Forkhead Transcription Factors - metabolism / Fundamental and applied biological sciences. Psychology / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Gene Knockdown Techniques / Genetic aspects / Glucose / Glucose metabolism / Glycolysis / Gynecology. Andrology. Obstetrics / Human Genetics / Humans / Internal Medicine / Kinases / Mammary gland diseases / Matrix metalloproteinase / Matrix Metalloproteinase 2 - genetics / Matrix Metalloproteinase 2 - metabolism / Medical sciences / Medicine / Medicine & Public Health / Metabolism / Metalloproteinase / Mice / Molecular and cellular biology / N-Acetylglucosamine / N-Acetylglucosaminyltransferases - antagonists & inhibitors / N-Acetylglucosaminyltransferases - deficiency / N-Acetylglucosaminyltransferases - genetics / N-Acetylglucosaminyltransferases - metabolism / Neoplasm Invasiveness - pathology / Oncogene Proteins - metabolism / Oncology / original-article / Phenotype / Physiological aspects / Post-translational modification / Proteins / RNA-mediated interference / Therapeutic targets / Transcription factors / Transferases / Tumorigenesis / Tumors / Up-Regulation - drug effects