Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Ma, Zhiyuan; Vosseller, Keith

doi:10.1074/jbc.r114.577718

Cited by 173 publications

(150 citation statements)

References 97 publications

Supporting

Mentioning

145

Contrasting

Order By: Relevance

“…The O-linked glycosylation of specific cellular substrates is known to affect various cellular processes, such as protein folding, cell adhesion, signal transduction, protein trafficking, cell proliferation, apoptosis, and cancer (2,49,50). At present, only a few specific substrates for GALNT3 have been identified.…”

Section: Discussionmentioning

confidence: 99%

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

Nakamura

Horie

Daidoji

et al. 2016

J Virol

View full text Add to dashboard Cite

Influenza A virus (IAV) affects the upper and lower respiratory tracts and rapidly induces the expression of mucins, which are common O-glycosylated proteins, on the epithelial surfaces of the respiratory tract. Although mucin production is associated with the inhibition of virus transmission as well as characteristic clinical symptoms, little is known regarding how mucins are produced on the surfaces of respiratory epithelial cells and how they affect IAV replication. In this study, we found that two microRNAs (miRNAs), miR-17-3p and miR-221, which target GalNAc transferase 3 (GALNT3) mRNA, are rapidly downregulated in human alveolar basal epithelial cells during the early stage of IAV infection. We demonstrated that the expression of GALNT3 mRNA is upregulated in an IAV replication-dependent fashion and leads to mucin production in bronchial epithelial cells. A lectin microarray analysis revealed that the stable expression of GALNT3 by human alveolar basal epithelial cells induces mucin-type O-glycosylation modifications similar to those present in IAV-infected cells, suggesting that GALNT3 promotes mucin-type O-linked glycosylation in IAV-infected cells. Notably, analyses using short interfering RNAs and miRNA mimics showed that GALNT3 knockdown significantly reduces IAV replication. Furthermore, IAV replication was markedly decreased in embryonic fibroblast cells obtained from galnt3-knockout mice. Interestingly, IAV-infected galnt3-knockout mice exhibited high mortality and severe pathological alterations in the lungs compared to those of wild-type mice. Our results demonstrate not only the molecular mechanism underlying rapid mucin production during IAV infection but also the contribution of O-linked glycosylation to the replication and propagation of IAV in lung cells. IMPORTANCEViral infections that affect the upper or lower respiratory tracts, such as IAV, rapidly induce mucin production on the epithelial surfaces of respiratory cells. However, the details of how mucin-type O-linked glycosylation is initiated by IAV infection and how mucin production affects viral replication have not yet been elucidated. In this study, we show that levels of two miRNAs that target the UDP-GalNAc transferase GALNT3 are markedly decreased during the early stage of IAV infection, resulting in the upregulation of GALNT3 mRNA. We also demonstrate that the expression of GALNT3 initiates mucin production and affects IAV replication in infected cells. This is the first report demonstrating the mechanism underlying the miRNA-mediated initiation of mucin-type O-glycosylation in IAV-infected cells and its role in viral replication. Our results have broad implications for understanding IAV replication and suggest a strategy for the development of novel anti-influenza approaches.

show abstract

Section: Discussionmentioning

confidence: 99%

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

Nakamura

Horie

Daidoji

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…Alterations in O-GlcNAc levels occur in several diseases, including heart failure, diabetes, cancer, and neurodegenerative disorders (1)(2)(3)(4)(5). Evidence suggests that changes in O-GlcNAc levels play a critical role in protein activity, stability, and localization (6 -9).…”

Section: The Posttranslational O-linked N-acetylglucosamine (O-mentioning

confidence: 99%

E2F1 Transcription Factor Regulates O-linked N-acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Expression

Muthusamy

Hong

Dassanayaka

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Protein O-GlcNAcylation, which is controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), has emerged as an important posttranslational modification that may factor in multiple diseases. Until recently, it was assumed that OGT/ OGA protein expression was relatively constant. Several groups, including ours, have shown that OGT and/or OGA expression changes in several pathologic contexts, yet the cis and trans elements that regulate the expression of these enzymes remain essentially unexplored. Here, we used a reporter-based assay to analyze minimal promoters and leveraged in silico modeling to nominate several candidate transcription factor binding sites in both Ogt (i.e. the gene for OGT protein) and Mgea5 (i.e. the gene for OGA protein). We noted multiple E2F binding site consensus sequences in both promoters. We performed chromatin immunoprecipitation in both human and mouse cells and found that E2F1 bound to candidate E2F binding sites in both promoters. In HEK293 cells, we overexpressed E2F1, which significantly reduced OGT and MGEA5 expression. Conversely, E2F1-deficient mouse fibroblasts had increased Ogt and Mgea5 expression. Of the known binding partners for E2F1, we queried whether retinoblastoma 1 (Rb1) might be involved. Rb1-deficient mouse embryonic fibroblasts showed increased levels of Ogt and Mgea5 expression, yet overexpression of E2F1 in the Rb1-deficient cells did not alter Ogt and Mgea5 expression, suggesting that Rb1 is required for E2F1-mediated suppression. In conclusion, this work identifies and validates some of the promoter elements for mouse Ogt and Mgea5 genes. Specifically, E2F1 negatively regulates both Ogt and Mgea5 expression in an Rb1 protein-dependent manner.2 modification occurs in a variety of cellular proteins and is known to be an important metabolic sensor in all metazoans. Alterations in O-GlcNAc levels occur in several diseases, including heart failure, diabetes, cancer, and neurodegenerative disorders (1-5). Evidence suggests that changes in O-GlcNAc levels play a critical role in protein activity, stability, and localization (6 -9). Using the substrate uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the enzyme O-GlcNAc transferase (OGT) adds the GlcNAc moiety to serine and threonine residues, whereas O-GlcNAcase (OGA) removes it. Embryonic lethality and developmental delay observed by genetic deletion of Ogt or Mgea5 demonstrates the critical role of these enzymes in O-GlcNAc cycling (10, 11). We (1), along with others (12-14), have observed alterations in the expression level of OGT and OGA protein along with concomitant protein O-GlcNAc modification in various pathological conditions. We recently reported that the up-regulation of miR-539 could be a mechanism for decreased OGA level in the infarcted mouse heart (15). Another study showed that increases in O-GlcNAc levels by pharmacological inhibition of OGA increased OGA expression through the O-GlcNAc modification of RNA polymerase II, whereas OGT levels decreased (13). Thus, changes in OGT/OGA protein e...

show abstract

“…Established role in synthesising O-GlcNAc which is elevated in numerous cancer types and has itself been described as a hallmark of cancer (Fardini et al 2013, Ma & Vosseller 2014 Over-expressed in prostate cancer and linked to increased synthesis of O-GlcNAc (Itkonen et al 2014). Over-expression of O-GlcNAc linked to poor prognosis (Kamigaito et al 2014).…”

Section: :3mentioning

confidence: 99%

“…Established role in synthesising O-GlcNAc which is elevated in numerous cancer types and has itself been described as a hallmark of cancer (Fardini et al 2013, Ma & Vosseller 2014 GNPNAT1 is decreased in CRPC (Kaushik et al 2016). Inhibition of HBP suggested as a potential therapy in CRPC (Kaushik et al 2016) Chondroitin sulfate synthesis CSGALNACT1 Initiation of chondroitin sulfate (CS) synthesis CS is a key molecule in cancer progression (Theocharis et al 2006).…”

Section: :3mentioning

confidence: 99%

“…Detected in patient serum and urine , Albitar et al 2016. HBP potential target in CRPC (Kaushik et al 2016) Established role in synthesising O-GlcNAc which is elevated in numerous cancer types and has itself been described as a hallmark of cancer (Fardini et al 2013, Ma & Vosseller 2014 Androgen regulated and linked to prostate cancer cell viability (Lee et al 2010. HBP is a potential target in CRPC (Kaushik et al 2016) GNPNAT1 Second enzyme in the hexosamine biosynthetic pathway (HBP)…”

Section: :3mentioning

confidence: 99%

See 1 more Smart Citation

Glycosylation is a global target for androgen control in prostate cancer cells

Munkley¹

2017

Endocrine-Related Cancer

View full text Add to dashboard Cite

Changes in glycan composition are common in cancer and can play important roles in all of the recognised hallmarks of cancer. We recently identified glycosylation as a global target for androgen control in prostate cancer cells and further defined a set of 8 glycosylation enzymes (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3), which are also significantly upregulated in prostate cancer tissue. These 8 enzymes are under direct control of the androgen receptor (AR) and are linked to the synthesis of important cancer-associated glycans such as sialyl-Tn (sTn), sialyl LewisX (SLeX), O-GlcNAc and chondroitin sulfate. Glycosylation has a key role in many important biological processes in cancer including cell adhesion, migration, interactions with the cell matrix, immune surveillance, cell signalling and cellular metabolism. Our results suggest that alterations in patterns of glycosylation via androgen control might modify some or all of these processes in prostate cancer. The prostate is an abundant secretor of glycoproteins of all types, and alterations in glycans are, therefore, attractive as potential biomarkers and therapeutic targets. Emerging data on these often overlooked glycan modifications have the potential to improve risk stratification and therapeutic strategies in patients with prostate cancer.

show abstract

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Cited by 173 publications

References 97 publications

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

E2F1 Transcription Factor Regulates O-linked N-acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Expression

Glycosylation is a global target for androgen control in prostate cancer cells

Contact Info

Product

Resources

About