Journal article
Critical Role of O-Linked β-N-Acetylglucosamine Transferase in Prostate Cancer Invasion, Angiogenesis, and Metastasis
The Journal of biological chemistry, v 287(14), pp 11070-11081
30 Mar 2012
PMID: 22275356
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Background:
Cancer cells display altered metabolism and expression of the nutrient sensor
O
-linked β-
N
-acetylglucosamine transferase (OGT).
Results:
Through regulation of FoxM1, OGT contributes to increased invasion, angiogenesis, and metastasis of prostate cancer cells.
Conclusion:
OGT plays a critical role in prostate cancer.
Significance:
OGT may provide a novel therapeutic target for treating prostate cancer.
Cancer cells universally increase glucose and glutamine consumption, leading to the altered metabolic state known as the Warburg effect; one metabolic pathway, highly dependent on glucose and glutamine, is the hexosamine biosynthetic pathway. Increased flux through the hexosamine biosynthetic pathway leads to increases in the post-translational addition of
O
-linked β-
N
-acetylglucosamine (
O
-GlcNAc) to various nuclear and cytosolic proteins. A number of these target proteins are implicated in cancer, and recently,
O
-GlcNAcylation was shown to play a role in breast cancer; however,
O
-GlcNAcylation in other cancers remains poorly defined. Here, we show that
O
-GlcNAc transferase (OGT) is overexpressed in prostate cancer compared with normal prostate epithelium and that OGT protein and
O
-GlcNAc levels are elevated in prostate carcinoma cell lines. Reducing
O
-GlcNAcylation in PC3-ML cells was associated with reduced expression of matrix metalloproteinase (MMP)-2, MMP-9, and VEGF, resulting in inhibition of invasion and angiogenesis. OGT-mediated regulation of invasion and angiogenesis was dependent upon regulation of the oncogenic transcription factor FoxM1, a key regulator of invasion and angiogenesis, as reducing OGT expression led to increased FoxM1 protein degradation. Conversely, overexpression of a degradation-resistant FoxM1 mutant abrogated OGT RNAi-mediated effects on invasion, MMP levels, angiogenesis, and VEGF expression. Using a mouse model of metastasis, we found that reduction of OGT expression blocked bone metastasis. Altogether, these data suggest that as prostate cancer cells alter glucose and glutamine levels,
O
-GlcNAc modifications and OGT levels become elevated and are required for regulation of malignant properties, implicating OGT as a novel therapeutic target in the treatment of cancer.
Metrics
Details
- Title
- Critical Role of O-Linked β-N-Acetylglucosamine Transferase in Prostate Cancer Invasion, Angiogenesis, and Metastasis
- Creators
- Thomas P Lynch - From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Christina M Ferrer - From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102S. RaElle Jackson - From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Kristina S Shahriari - From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Keith Vosseller - From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Mauricio J Reginato - From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102
- Publication Details
- The Journal of biological chemistry, v 287(14), pp 11070-11081
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- R01 CA155413 / National Institutes of Health
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000302780100035
- Scopus ID
- 2-s2.0-84859484538
- Other Identifier
- 991014877936904721
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InCites Highlights
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- Web of Science research areas
- Biochemistry & Molecular Biology