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Miao Y, Zhang T, Ma Z, Du H, Gu Q, Jiang M, Xiong K, Liu CF, Meng H. Modulation of O-GlcNAc cycling influences α-synuclein amplification, degradation, and associated neuroinflammatory pathology. Molecular neurodegeneration 2025 20(1) 41146299
Abstract:
The accumulation and propagation of α-synuclein (α-syn) are hallmark features of Parkinson's disease (PD) and related neurodegenerative disorders. O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering α-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and α-syn aggregation and the propagation of amyloid pathology is not well elucidated.
O-GlcNAc proteins:
SYUA
Species: Homo sapiens
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Singh JP, Qian K, Lee JS, Zhou J, Han X, Zhang B, Ong Q, Ni W, Jiang M, Ruan HB, Li MD, Zhang K, Ding Z, Lee P, Singh K, Wu J, Herzog RI, Kaech S, Wendel HG, Yates JR 3rd, Han W, Sherwin RS, Nie Y, Yang X. O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth. Oncogene 2020 39(3) 31501520
Abstract:
Cancer cells are known to adopt aerobic glycolysis in order to fuel tumor growth, but the molecular basis of this metabolic shift remains largely undefined. O-GlcNAcase (OGA) is an enzyme harboring O-linked β-N-acetylglucosamine (O-GlcNAc) hydrolase and cryptic lysine acetyltransferase activities. Here, we report that OGA is upregulated in a wide range of human cancers and drives aerobic glycolysis and tumor growth by inhibiting pyruvate kinase M2 (PKM2). PKM2 is dynamically O-GlcNAcylated in response to changes in glucose availability. Under high glucose conditions, PKM2 is a target of OGA-associated acetyltransferase activity, which facilitates O-GlcNAcylation of PKM2 by O-GlcNAc transferase (OGT). O-GlcNAcylation inhibits PKM2 catalytic activity and thereby promotes aerobic glycolysis and tumor growth. These studies define a causative role for OGA in tumor progression and reveal PKM2 O-GlcNAcylation as a metabolic rheostat that mediates exquisite control of aerobic glycolysis.
O-GlcNAc proteins:
KPYM
Species: Homo sapiens
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Chu Y, Jiang M, Wu N, Xu B, Li W, Liu H, Su S, Shi Y, Liu H, Gao X, Fu X, Chen D, Li X, Wang W, Liang J, Nie Y, Fan D. O-GlcNAcylation of SIX1 enhances its stability and promotes Hepatocellular Carcinoma Proliferation. Theranostics 2020 10(21) 32863962
Abstract:
It is universally accepted that aberrant metabolism facilitates tumor growth. However, how cancer cells coordinate glucose metabolism and tumor proliferation is largely unknown. Sine oculis homeobox homolog 1 (SIX1) is a transcription factor that belongs to the SIX family and is believed to play an important role in the regulation of the Warburg effect in tumors. However, whether the role of SIX1 and the molecular mechanisms that regulate its activity are similar in hepatocellular carcinoma (HCC) still needs further investigation. Methods: Western blotting was performed to determine the levels of SIX1 and O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) in HCC tissues. Cell Counting Kit 8 (CCK8), colony formation and mouse tumor model assays were used to establish the role of SIX1 and O-GlcNAcylation in HCC processes. Mass spectrometry, immunoprecipitation and site-directed mutagenesis were performed to confirm the O-GlcNAcylation of SIX1. Results: Here, we demonstrated that SIX1, the key transcription factor regulating the Warburg effect in cancer, promotes HCC growth in vitro and in vivo. Furthermore, we revealed that SIX1 could also enhance the levels of a posttranslational modification called O-GlcNAcylation. Importantly, we found that SIX1 was also highly modified by O-GlcNAcylation and that O-GlcNAcylation inhibited the ubiquitination degradation of SIX1. In addition, site-directed mutagenesis at position 276 (T276A) decreased the O-GlcNAcylation level and reversed the protumor effect of SIX1. Conclusions: We conclude that O-GlcNAcylation of SIX1 enhances its stability and promotes HCC proliferation. Our findings illustrate a novel feedback loop of SIX1 and O-GlcNAcylation and show that O-GlcNAcylation of SIX1 is an important way to coordinate glucose metabolism and tumor progression.
O-GlcNAc proteins:
SIX1
Species: Homo sapiens
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Jiang M, Xu B, Li X, Shang Y, Chu Y, Wang W, Chen D, Wu N, Hu S, Zhang S, Li M, Wu K, Yang X, Liang J, Nie Y, Fan D. O-GlcNAcylation promotes colorectal cancer metastasis via the miR-101-O-GlcNAc/EZH2 regulatory feedback circuit. Oncogene 2019 38(3) 30093632
Abstract:
Advanced colorectal cancer (CRC) is one of the deadliest cancers, and the 5-year survival rate of patients with metastasis is extremely low. The epithelial-mesenchymal transition (EMT) is considered essential for metastatic CRC, but the fundamental molecular basis underlying this effect remains unknown. Here, we identified that O-GlcNAcylation, a unique posttranslational modification (PTM) involved in cancer metabolic reprogramming, increased the metastatic capability of CRC. The levels of O-GlcNAcylation were increased in the metastatic CRC tissues and cell lines, which likely promoted the EMT by enhancing EZH2 protein stability and function. The CRC patients with higher levels of O-GlcNAcylation exhibited greater lymph node metastasis potential and lower overall survival. Bioinformatic analysis and luciferase reporter assays revealed that both O-GlcNAcylation transferase (OGT) and EZH2 are posttranscriptionally inhibited by microRNA-101. In addition, O-GlcNAcylation and H3K27me3 modification in the miR-101 promoter region further inhibited the transcription of miR-101, resulting in the upregulation of OGT and EZH2 in metastatic CRC, thus forming a vicious cycle. In this study, we demonstrated that O-GlcNAcylation, which is negatively regulated by microRNA-101, likely promotes CRC metastasis by enhancing EZH2 protein stability and function. Reducing O-GlcNAcylation may be a potential therapeutic strategy for metastatic CRC.
O-GlcNAc proteins:
EZH2
Species: Homo sapiens
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Jiang M, Wu N, Xu B, Chu Y, Li X, Su S, Chen D, Li W, Shi Y, Gao X, Zhang H, Zhang Z, Du W, Nie Y, Liang J, Fan D. Fatty acid-induced CD36 expression via O-GlcNAcylation drives gastric cancer metastasis. Theranostics 2019 9(18) 31410220
Abstract:
Metastasis is the primary cause of death in patients with advanced cancer. Recently, a high-fat diet was shown to specifically promote the metastatic potential of specific cancer cells in a CD36-dependent manner. However, the molecular basis of the fatty acid (FA)-induced upregulation of CD36 has remained unclear. Methods: RT-qPCR, FACS analysis, immunoblotting and immunohistochemistry, as well as retrieving TCGA database, were carried out to quantitate CD36 expression in gastric cancer (GC) tissues and cell lines. Transwell assay and xenografts were used to assess cell metastasis abilities in vitro and in vivo after indicated treatment. Luciferase reporter assay was carried out to evaluate the changes in signaling pathways when O-GlcNAcylation level was increased in GC cells and in vitro O-GlcNAcylation assay was utilized for wild and mutant types of CD36 protein to explore the potential O-GlcNAcylation sites. Results: High CD36 expression is a predictor of poor survival and promotes metastasis of GC cells and the use of neutralizing antibodies to block CD36 inhibits GC metastasis in mice. FA or a HFD promotes the metastatic potential of GC cells by upregulating CD36 via increasing the O-GlcNAcylation level. Increased O-GlcNAcylation levels promote the transcription of CD36 by activating the NF-κB pathway and also increase its FA uptake activity by directly modifying CD36 at S468 and T470. Conclusion: FA-induced hyper-O-GlcNAcylation promotes the transcription and function of CD36 by activating the NF-κB pathway and directly modifying CD36 at S468 and T470, which drives GC metastasis.
O-GlcNAc proteins:
CD36
Species: Homo sapiens
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Wu N, Jiang M, Han Y, Liu H, Chu Y, Liu H, Cao J, Hou Q, Zhao Y, Xu B, Xie X. O-GlcNAcylation promotes colorectal cancer progression by regulating protein stability and potential catcinogenic function of DDX5. Journal of cellular and molecular medicine 2019 23(2) 30484950
Abstract:
The RNA helicase p68 (DDX5), a key player in RNA metabolism, belongs to the DEAD box family and is involved in the development of colorectal cancer. Here, we found both DDX5 and O-GlcNAcylation are up-regulated in colorectal cancer. In addition, DDX5 protein level is significantly positively correlated with the expression of O-GlcNAcylation. Although it was known DDX5 protein could be regulated by post-translational modification (PTM), how O-GlcNAcylation modification regulated of DDX5 remains unclear. Here we show that DDX5 interacts directly with OGT in the SW480 cell line, which is the only known enzyme that catalyses O-GlcNAcylation in humans. Meanwhile, O-GlcNAcylation could promote DDX5 protein stability. The OGT-DDX5 axis affects colorectal cancer progression mainly by regulating activation of the AKT/mTOR signalling pathway. Taken together, these results indicated that OGT-mediated O-GlcNAcylation stabilizes DDX5, promoting activation of the AKT/mTOR signalling pathway, thus accelerating colorectal cancer progression. This study not only reveals the novel functional of O-GlcNAcylation in regulating DDX5, but also reveals the carcinogenic effect of the OGT-DDX5 axis in colorectal cancer.
O-GlcNAc proteins:
DDX5
Species: Homo sapiens
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Jiang MS, Hart GW. A subpopulation of estrogen receptors are modified by O-linked N-acetylglucosamine. The Journal of biological chemistry 1997 272(4) 8999954
Abstract:
Estrogen receptors (ER) are ligand-inducible transcription factors regulated by Ser(Thr)-O-phosphorylation. Many transcription factors and eukaryotic RNA polymerase II itself are also dynamically modified by Ser(Thr)-O-linked N-acetylglucosamine moieties (O-GlcNAc). Here we report that subpopulations of murine, bovine, and human estrogen receptors are modified by O-GlcNAc. O-GlcNAc moieties were detected on insect cell-expressed, mouse ER (mER) by probing with bovine milk galactosyltransferase, followed by structural analysis. Wheat germ agglutinin-Sepharose affinity chromatography also readily detected terminal GlcNAc residues on subpopulations of ER purified from calf uterus, from human breast cancer cells (MCF-7), or from mER produced by in vitro translation. These data suggest that greater than 10% of these populations of estrogen receptors bear O-GlcNAc. Site mapping of insect cell expressed mER localized one major site of O-GlcNAc addition to Thr-575, within a PEST region of the carboxyl-terminal F domain. Based upon their relative resistance to both hexosaminidase and to in vitro galactosylation, O-GlcNAc moieties appear to be largely buried on native mER. This dynamic saccharide modification, like phosphorylation, may play a role in modulating the dimerization, stability, or transactivation functions of estrogen receptors.
O-GlcNAc proteins:
ESR1, ESR1, ESR1
Species: Mus musculus, Bos taurus, Homo sapiens
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