Journal article
Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1
Oncogene, v 29(19), pp 2831-2842
01 May 2010
PMID: 20190804
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 metallo-proteinase- 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.
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Details
- Title
- Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1
- Creators
- S. A. Caldwell - Drexel University, Biochemistry and Molecular BiologyS. R. Jackson - Drexel University, Biochemistry and Molecular BiologyK. S. Shahriari - Drexel University, Biochemistry and Molecular BiologyT. P. Lynch - Drexel University, Biochemistry and Molecular BiologyG. Sethi - Drexel University, Biochemistry and Molecular BiologyS. Walker - Harvard UniversityK. Vosseller - Drexel University, Biochemistry and Molecular BiologyM. J. Reginato - Drexel University, Biochemistry and Molecular Biology
- Publication Details
- Oncogene, v 29(19), pp 2831-2842
- Publisher
- Springer Nature
- Number of pages
- 12
- Grant note
- BC086596; BC074374 / Department of Defense; United States Department of Defense
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000277591900008
- Scopus ID
- 2-s2.0-77952429792
- Other Identifier
- 991019167838904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Genetics & Heredity
- Oncology