Critical Role of O-Linked β-N-Acetylglucosamine Transferase in Prostate Cancer Invasion, Angiogenesis, and Metastasis

Lynch, Thomas P.; Ferrer, Christina M.; Jackson, Susan; Shahriari, Kristina; Vosseller, Keith; Reginato, Mauricio J.

doi:10.1074/jbc.m111.302547

Cited by 244 publications

(281 citation statements)

References 45 publications

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“…Our observation of higher O-GlcNAc levels in activated T cells, which undergo rapid division, suggests that O-GlcNAc levels are positively correlated with cell proliferation. Indeed, elevated O-GlcNAc levels also were reported in cancer (31,66,67). Consistent with previous work using genetic approaches (25,38), we show in this study with a specific inhibitor that OGT is important for T cell function, because blocking its activity suppressed IL-2 production and cell proliferation.…”

Section: Discussionsupporting

confidence: 92%

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Lund

Elias

Davis

2016

The Journal of Immunology

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T cell activation in response to Ag is largely regulated by protein posttranslational modifications. Although phosphorylation has been extensively characterized in T cells, much less is known about the glycosylation of serine/threonine residues by O-linked N-acetylglucosamine (O-GlcNAc). Given that O-GlcNAc appears to regulate cell signaling pathways and protein activity similarly to phosphorylation, we performed a comprehensive analysis of O-GlcNAc during T cell activation to address the functional importance of this modification and to identify the modified proteins. Activation of T cells through the TCR resulted in a global elevation of O-GlcNAc levels and in the absence of O-GlcNAc, IL-2 production and proliferation were compromised. T cell activation also led to changes in the relative expression of O-GlcNAc transferase (OGT) isoforms and accumulation of OGT at the immunological synapse of murine T cells. Using a glycoproteomics approach, we identified >200 O-GlcNAc proteins in human T cells. Many of the identified proteins had a functional relationship to RNA metabolism, and consistent with a connection between O-GlcNAc and RNA, inhibition of OGT impaired nascent RNA synthesis upon T cell activation. Overall, our studies provide a global analysis of O-GlcNAc dynamics during T cell activation and the first characterization, to our knowledge, of the O-GlcNAc glycoproteome in human T cells.

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Section: Discussionsupporting

confidence: 92%

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Lund

Elias

Davis

2016

The Journal of Immunology

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“…Consistent with this, reducing hyper-O-GlcNAcylation decreases cell cycle progression in breast and prostate cancer (7,9). Cyclin D 1 is a positive regulator of the G 1 /S transition.…”

Section: O-glcnac and Cancer Cell Proliferationsupporting

confidence: 50%

“…Emerging evidence suggests that hyper-O-GlcNAcylation in cancers may be involved in tumor invasion and metastasis. Whereas increasing hyper-O-GlcNAcylation enhances the migration/invasion of breast and liver cancer cells, lowering hyper-O-GlcNAcylation by knockdown of OGT inhibits tumor invasion and metastasis in vivo and in vitro in breast and prostate cancer cells (7)(8)(9)78). The mechanisms by which hyper-O-GlcNAcylation may regulate tumor invasion and metastasis are only beginning to be understood.…”

Section: O-glcnac and Cancer Cell Invasion And Metastasismentioning

confidence: 99%

“…Recent evidence indicates that tumor angiogenesis may be supported in part by hyper-O-GlcNAcylation. Reducing hyper-OGlcNAcylation in the prostate cancer cell line PC-3ML by knocking down OGT inhibits VEGF expression and in vitro angiogenesis (9). To sustain angiogenesis, the tumor stroma requires continuous remodeling, a process in which matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9 are vital in the proteolytic degradation of the extracellular matrix (74).…”

Section: O-glcnac and Cancer Angiogenesismentioning

confidence: 99%

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Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Vosseller

2014

Journal of Biological Chemistry

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173

140

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O-Linked ␤-N-acetylglucosamine (O-GlcNAc) is a carbohydrate post-translational modification on hydroxyl groups of serine and/or threonine residues of cytosolic and nuclear proteins. Analogous to phosphorylation, O-GlcNAcylation plays crucial regulatory roles in cellular signaling. Recent work indicates that increased O-GlcNAcylation is a general feature of cancer and contributes to transformed phenotypes. In this minireview, we discuss how hyper-O-GlcNAcylation may be linked to various hallmarks of cancer, including cancer cell proliferation, survival, invasion, and metastasis; energy metabolism; and epigenetics. We also discuss potential therapeutic modulation of O-GlcNAc levels in cancer treatment.

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“…Therefore, the use of angiogenic inhibitors in order to reduce tumor metastasis is a promising method for treating tumors (O'Reilly et al, 1994;Konno et al, 1995;Zetter, 1998;Ebos et al, 2009;Pàez-Ribes et al, 2009). Prostate cancer is related to angiogenesis and vascular invasion and thus inhibition of angiogenesis can be used as a method to treat prostate cancers (Weidner et al, 1993;Bagley et al, 2011;Gyftopoulos et al, 2011;Assadian et al, 2012;Lynch et al, 2012;Pande et al, 2012;Pinto et al, 2012). We previously found that ApoG2, a gossypol derivative, inhibits proliferation of prostate cancer cells both in vitro and in vivo and induces their apoptosis and autophagy (Zhang et al, 2010a;Zhang et al, 2010b).…”

Section: Introductionmentioning

confidence: 99%