O-GlcNAc Transferase Integrates Metabolic Pathways to Regulate the Stability of c-MYC in Human Prostate Cancer Cells

Itkonen, Harri M.; Minner, Sarah; Guldvik, Ingrid Jenny; Sandmann, Mareike Julia; Tsourlakis, Maria Christina; Berge, Viktor; Svindland, Aud; Schlomm, Thorsten; Mills, Ian G.

doi:10.1158/0008-5472.can-13-0549

Cited by 247 publications

(259 citation statements)

References 43 publications

(61 reference statements)

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“…These results suggest that O-GlcNAc could affect the oncogenic activities of HPV16 E6/E7. Similar alterations in the MEFs with or without HPV E6/E7 were also observed after exposure to 50 μM ST045849 [3-(2-adamantanylethyl)-2-[(4-chlorophenyl)azamethylene]-4-oxo-1,3-thiazaperhydroine-6-carboxylic acid], which inhibits OGT specifically (23)(24)(25) (Figs. S5B and S6).…”

supporting

confidence: 63%

“…The basis for substrate specificity of O-GlcNAc is unclear, making the identification of key substrates challenging. However, c-MYC, an oncogenic transcriptional factor, is known to be O-GlcNAcylated (12,13,25). To examine whether c-MYC and other cellular factors known to be activated by HPVs are O-GlcNAcylated due to the induction of OGT by HPV E6 or E6/E7, we used wheat germ agglutinin affinity purification to pull down O-GlcNAc proteins from MEF/GFP (control) and MEF/HPV16 oncogenes.…”

Section: Suppression Of O-glcnacylation Impedes Tumor Growth and Metamentioning

confidence: 99%

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O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

Zeng

Zhao

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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High-risk human papillomaviruses (HPVs) are causative agents of anogenital cancers and a fraction of head and neck cancers. The mechanisms involved in the progression of HPV neoplasias to cancers remain largely unknown. Here, we report that O-linked GlcNAcylation (O-GlcNAc) and O-GlcNAc transferase (OGT) were markedly increased in HPV-caused cervical neoplasms relative to normal cervix, whereas O-GlcNAcase (OGA) levels were not altered. Transduction of HPV16 oncogene E6 or E6/E7 into mouse embryonic fibroblasts (MEFs) up-regulated OGT mRNA and protein, elevated the level of O-GlcNAc, and promoted cell proliferation while reducing cellular senescence. Two HR HPV genes, E6 and E7, are potent oncogenes based on their immortalizing and transforming activities in cell culture systems and their capacities to induce tumors in animal models. The HR HPV E7 oncoprotein binds to more than 20 cellular targets and interferes with multiple cellular processes, leading to deregulated cell cycle, centrosome amplification, DNA damage, anoikis resistance, anchorage-independent cell growth and malignant transformation as well as immune surveillance evasion.

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supporting

confidence: 63%

Section: Suppression Of O-glcnacylation Impedes Tumor Growth and Metamentioning

confidence: 99%

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

Zeng

Zhao

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The transcription factor c-myc is clearly essential for increased O-GlcNAc levels in activated T cells (85), probably due, in part, to its role in driving expression of nutrient transporters (75). At the same time, OGT activity is critical for stabilizing c-myc expression (35,87). Our results showing reduced RNA synthesis in human T cells treated with the OGT inhibitor (Fig.…”

Section: Discussionmentioning

confidence: 53%

“…Furthermore, conditional deletion of OGT results in cellular senescence and apoptosis in numerous cell types, including T cells (25). Considering that abnormal O-GlcNAc levels, possibly stemming from alterations in metabolism (26)(27)(28)(29), may contribute to the pathology of several diseases, including cancer, diabetes, and neurodegeneration (29)(30)(31)(32)(33)(34)(35)(36), a greater understanding of O-GlcNAc biology in T cells could help to explain the impact of metabolic health on the function of the immune system.making the relevance to primary T cells unclear. Furthermore, only a selected few proteins were surveyed.…”

mentioning

confidence: 99%

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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“…These enzymes control the activity of glucocorticoids [80]. Glucocorticoids promote gluconeogenesis, but in liver cancer cells the altered expression of 11β-hydroxysteroid dehydrogenase1/2 results in the insensitiveness of liver cancer cells to endogenous glucocorticoids [81]. Moreover, it was shown that Stat3-mediated activation of the microRNA23a suppresses gluconeogenesis by targeting glucose-6-phosphatase expression [79].…”

Section: Metabolic Alterations In Liver Cancermentioning

confidence: 99%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

104

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KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

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O-GlcNAc Transferase Integrates Metabolic Pathways to Regulate the Stability of c-MYC in Human Prostate Cancer Cells

Cited by 247 publications

References 43 publications

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

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

Organ-Specific Cancer Metabolism and Its Potential for Therapy

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