Fatty acid synthase inhibits the O-GlcNAcase during oxidative stress

Groves, Jennifer; Maduka, Austin; O’Meally, Robert N.; Cole, Robert N.; Zachara, Natasha E.

doi:10.1074/jbc.m116.760785

Cited by 56 publications

(57 citation statements)

References 90 publications

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“…Prior proteomic analysis has focused on discovery of OGT substrates, leading to more than 4,000 O-GlcNAc-modified proteins identified to date (50). Many of these proteins have links to DNA damage and repair and their dynamic O-GlcNAcylation is implicated in the cellular response to diverse forms of stress (23,(51)(52)(53). Despite many leads, functional analysis has lagged considerably, leaving roles for O-GlcNAcylation in DDR poorly defined.…”

Section: Discussionmentioning

confidence: 99%

O-GlcNAcylation Enhances Double-Strand Break Repair, Promotes Cancer Cell Proliferation, and Prevents Therapy-Induced Senescence in Irradiated Tumors

Efimova

Appelbe

Ricco

et al. 2019

Molecular Cancer Research

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The metabolic reprogramming associated with characteristic increases in glucose and glutamine metabolism in advanced cancer is often ascribed to answering a higher demand for metabolic intermediates required for rapid tumor cell growth. Instead, recent discoveries have pointed to an alternative role for glucose and glutamine metabolites as cofactors for chromatin modifiers and other protein posttranslational modification enzymes in cancer cells. Beyond epigenetic mechanisms regulating gene expression, many chromatin modifiers also modulate DNA repair, raising the question whether cancer metabolic reprogramming may mediate resistance to genotoxic therapy and genomic instability. Our prior work had implicated N-acetyl-glucosamine (GlcNAc) formation by the hexosamine biosynthetic pathway (HBP) and resulting protein O-GlcNAcylation as a common means by which increased glucose and glutamine metabolism can drive double-strand break (DSB) repair and resistance to therapyinduced senescence in cancer cells. We have examined the effects of modulating O-GlcNAcylation on the DNA damage response (DDR) in MCF7 human mammary carcinoma in vitro and in xenograft tumors. Proteomic profiling revealed deregulated DDR pathways in cells with altered O-GlcNAcylation. Promoting protein O-GlcNAc modification by targeting O-GlcNAcase or simply treating animals with GlcNAc protected tumor xenografts against radiation. In turn, suppressing protein O-GlcNAcylation by blocking O-GlcNAc transferase activity led to delayed DSB repair, reduced cell proliferation, and increased cell senescence in vivo. Taken together, these findings confirm critical connections between cancer metabolic reprogramming, DDR, and senescence and provide a rationale to evaluate agents targeting O-GlcNAcylation in patients as a means to restore tumor sensitivity to radiotherapy. Implications: The finding that the HBP, via its impact on protein O-GlcNAcylation, is a key determinant of the DDR in cancer provides a mechanistic link between metabolic reprogramming, genomic instability, and therapeutic response and suggests novel therapeutic approaches for tumor radiosensitization.

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Section: Discussionmentioning

confidence: 99%

O-GlcNAcylation Enhances Double-Strand Break Repair, Promotes Cancer Cell Proliferation, and Prevents Therapy-Induced Senescence in Irradiated Tumors

Efimova

Appelbe

Ricco

et al. 2019

Molecular Cancer Research

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“…OGA activity assay was performed as described previously (58). Briefly, duplicate 50-l reactions containing whole cell lysate, 50 mM sodium cacodylate, pH 6.4, 0.3% BSA, 100 mM N-acetyl-D-galactosamine (GalNAc), and 1 mM 4-methylumbelliferyl (4MU)-GlcNAc or 4MU-GalNAc (Sigma) were set up in black flat-bottomed 96-well plates.…”

Section: Oga Activity Assaymentioning

confidence: 99%

Transcriptional regulation of O-GlcNAc homeostasis is disrupted in pancreatic cancer

Qian

Wang

et al. 2018

Journal of Biological Chemistry

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Many intracellular proteins are reversibly modified by -linked GlcNAc (-GlcNAc), a post-translational modification that dynamically regulates fundamental cellular processes in response to diverse environmental cues. Accumulating evidence indicates that both excess and deficiency of protein -GlcNAcylation can have deleterious effects on the cell, suggesting that maintenance of-GlcNAc homeostasis is essential for proper cellular function. However, the mechanisms through which -GlcNAc homeostasis is maintained in the physiologic state and altered in the disease state have not yet been investigated. Here, we demonstrate the existence of a homeostatic mechanism involving mutual regulation of the-GlcNAc-cycling enzymes -GlcNAc transferase (OGT) and-GlcNAcase (OGA) at the transcriptional level. Specifically, we found that OGA promotes transcription through cooperation with the histone acetyltransferase p300 and transcription factor CCAAT/enhancer-binding protein β (C/EBPβ). To examine the role of mutual regulation of OGT and OGA in the disease state, we analyzed gene expression data from human cancer data sets, which revealed that and expression levels are highly correlated in numerous human cancers, particularly in pancreatic adenocarcinoma. Using a -driven primary mouse pancreatic ductal adenocarcinoma (PDAC) cell line, we found that inhibition of extracellular signal-regulated kinase (ERK) signaling decreases OGA glycosidase activity and reduces OGT mRNA and protein levels, suggesting that ERK signaling may alter -GlcNAc homeostasis in PDAC by modulating OGA-mediated transcription. Our study elucidates a transcriptional mechanism that regulates cellular -GlcNAc homeostasis, which may lay a foundation for exploring-GlcNAc signaling as a therapeutic target for human disease.

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“…One study combined this with stable isotopicl abeling of amino acids in cell culture (SILAC) to analyze the proteins enriched by OGA quantitatively. [76] They identified 90 proteins that were potential interacting partners of OGA and validatedt hat one of them,f attya cid synthase, reduces OGA activity upon binding. Some considerations should be taken into account forO GA BioID methods.…”

Section: Engineered Oga For Enriching Glycoprotein Substrates and Binmentioning

confidence: 99%

Chemical and Biochemical Strategies To Explore the Substrate Recognition of O‐GlcNAc‐Cycling Enzymes

Worth

et al. 2018

ChemBioChem

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The O-linked N-acetylglucosamine (O-GlcNAc) modification is an essential component in cell regulation. A single pair of human enzymes conducts this modification dynamically on a broad variety of proteins: O-GlcNAc transferase (OGT) adds the GlcNAc residue and O-GlcNAcase (OGA) hydrolyzes it. This modification is dysregulated in many diseases, but its exact effect on particular substrates remains unclear. In addition, no apparent sequence motif has been found in the modified proteins, and the factors controlling the substrate specificity of OGT and OGA are largely unknown. In this minireview, we will discuss recent developments in chemical and biochemical methods toward addressing the challenge of OGT and OGA substrate recognition. We hope that the new concepts and knowledge from these studies will promote research in this area to advance understanding of O-GlcNAc regulation in health and disease.

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Fatty acid synthase inhibits the O-GlcNAcase during oxidative stress

Cited by 56 publications

References 90 publications

O-GlcNAcylation Enhances Double-Strand Break Repair, Promotes Cancer Cell Proliferation, and Prevents Therapy-Induced Senescence in Irradiated Tumors

O-GlcNAcylation Enhances Double-Strand Break Repair, Promotes Cancer Cell Proliferation, and Prevents Therapy-Induced Senescence in Irradiated Tumors

Transcriptional regulation of O-GlcNAc homeostasis is disrupted in pancreatic cancer

Chemical and Biochemical Strategies To Explore the Substrate Recognition of O‐GlcNAc‐Cycling Enzymes

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