Increased SUMO-activating enzyme SAE1/UBA2 promotes glycolysis and pathogenic behavior of rheumatoid fibroblast-like synoviocytes

Wang, Cuicui; Xiao, Youjun; Lao, Minxi; Wang, Jingnan; Xu, Siqi; Li, Ruiru; Xu, Xuanxian; Yu, Kuang; Shi, Maohua; Zou, Yaoyao; Wang, Qingwen; Liang, Liuqin; Zheng, Song Guo; Xu, Hanshi

doi:10.1172/jci.insight.135935

Cited by 33 publications

(29 citation statements)

References 51 publications

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“…Oxidative stress is a contributing factor in the pathogenesis of RA and influences the development of the RA process through multiple pathways (133,134). RA as an autoimmune disease and SUMOylation is a novel pathway involving its phenotypic differences (135) and ubiquitin like modifier activating enzyme 2 (UBA2) in FLSs and ST of patients with RA, where SAE1/UBA2 regulated the glycolytic pathway and biological functions of the RA FLSs through SUMOylation-mediated PKM2 phosphorylation (123). For instance, in lung cancer cells, SUMO1 promotes PKM2dependent glycolysis.…”

Section: Pkm2mentioning

confidence: 99%

“…PK expression was high in RA synovial cells, indicating that RA STs present increased glycolytic activity ( 122 ). Phosphorylated PKM2 (p-PKM2) expression is increased in FLSs and the ST of patients with RA ( 123 ). PKM2 expression is higher in the lining and sublining layer, and vascular system of the RA ST than in the OA ST ( 124 ).…”

Section: Pkm2mentioning

confidence: 99%

“…PKM2 expression is higher in the lining and sublining layer, and vascular system of the RA ST than in the OA ST ( 124 ). siRNA transfection of PKM2 results in decreased expression of PKM2 and p-PKM2, which in turn results in decreased migration, invasion, expression of inflammatory factors (such as IL-1β, IL-6, and IL-8), glucose uptake and lactate secretion, and expression of LDHA, PDK1, and GLUT1 ( 123 ). Studies have described an altered glucose metabolism in RA.…”

Section: Pkm2mentioning

confidence: 99%

“…Wang C et al. found increased expression of SUMO-activating enzyme subunit 1 (SAE1) and ubiquitin like modifier activating enzyme 2 (UBA2) in FLSs and ST of patients with RA, where SAE1/UBA2 regulated the glycolytic pathway and biological functions of the RA FLSs through SUMOylation-mediated PKM2 phosphorylation ( 123 ). For instance, in lung cancer cells, SUMO1 promotes PKM2-dependent glycolysis.…”

Section: Pkm2mentioning

confidence: 99%

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Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis

et al. 2021

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Rheumatoid arthritis (RA) is a classic autoimmune disease characterized by uncontrolled synovial proliferation, pannus formation, cartilage injury, and bone destruction. The specific pathogenesis of RA, a chronic inflammatory disease, remains unclear. However, both key glycolysis rate-limiting enzymes, hexokinase-II (HK-II), phosphofructokinase-1 (PFK-1), and pyruvate kinase M2 (PKM2), as well as indirect rate-limiting enzymes, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), are thought to participate in the pathogenesis of RA. In here, we review the latest literature on the pathogenesis of RA, introduce the pathophysiological characteristics of HK-II, PFK-1/PFKFB3, and PKM2 and their expression characteristics in this autoimmune disease, and systematically assess the association between the glycolytic rate-limiting enzymes and RA from a molecular level. Moreover, we highlight HK-II, PFK-1/PFKFB3, and PKM2 as potential targets for the clinical treatment of RA. There is great potential to develop new anti-rheumatic therapies through safe inhibition or overexpression of glycolysis rate-limiting enzymes.

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Section: Pkm2mentioning

confidence: 99%

Section: Pkm2mentioning

confidence: 99%

Section: Pkm2mentioning

confidence: 99%

Section: Pkm2mentioning

confidence: 99%

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Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis

et al. 2021

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“…SAE1 has a molecular weight of 110 kDa, predominantly localizes to the nucleus and can be found in a variety of tissues. SAE1 forms a thioester bond between SUMO protein and UBA2/SAE2 by regulating the activation of ATP-dependent SUMO protein, and then participates in the process of SUMO protein modification ( Amente et al, 2012 ; Yang et al, 2019 ; Wang et al, 2020 ; Ong et al, 2021 ). SAE1 mainly mediates acetylation and phosphorylation and plays an important role in chromosome division and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

The Expression and Prognostic Value of SUMO1-Activating Enzyme Subunit 1 and Its Potential Mechanism in Triple-Negative Breast Cancer

Wang

Zhong

Deng³

et al. 2021

Front. Cell Dev. Biol.

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Background: Triple-negative breast cancer (TNBC) is the most invasive and metastatic subtype of breast cancer. SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme, is indispensable for protein SUMOylation. SAE1 has been found to be a relevant biomarker for progression and prognosis in several tumor types. However, the role of SAE1 in TNBC remains to be elucidated.Methods: In the research, the mRNA expression of SAE1 was analyzed via the cancer genome atlas (TCGA) and gene expression omnibus (GEO) database. Cistrome DB Toolkit was used to predict which transcription factors (TFs) are most likely to increase SAE1 expression in TNBC. The correlation between the expression of SAE1 and the methylation of SAE1 or quantity of tumor-infiltrating immune cells was further invested. Single-cell analysis, using CancerSEA, was performed to query which functional states are associated with SAE1 in different cancers in breast cancer at the single-cell level. Next, weighted gene coexpression network (WGCNA) was applied to reveal the highly correlated genes and coexpression networks of SAE1 in TNBC patients, and a prognostic model containing SAE1 and correlated genes was constructed. Finally, we also examined SAE1 protein expression of 207 TNBC tissues using immunohistochemical (IHC) staining.Results: The mRNA and protein expression of SAE1 were increased in TNBC tissues compared with adjacent normal tissues, and the protein expression of SAE1 was significantly associated with overall survival (OS) and disease-free survival (DFS). Correlation analyses revealed that SAE1 expression was positively correlated with forkhead box M1 (FOXM1) TFs and negatively correlated with SAE1 methylation site (cg14042711) level. WGCNA indicated that the genes coexpressed with SAE1 belonged to the green module containing 1,176 genes. Through pathway enrichment analysis of the module, 1,176 genes were found enriched in cell cycle and DNA repair. Single-cell analysis indicated that SAE1 and its coexpression genes were associated with cell cycle, DNA damage, DNA repair, and cell proliferation. Using the LASSO COX regression, a prognostic model including SAE1 and polo-like kinase 1 (PLK1) was built to accurately predict the likelihood of DFS in TNBC patients.Conclusion: In conclusion, we comprehensively analyzed the mRNA and protein expression, prognosis, and interaction genes of SAE1 in TNBC and constructed a prognostic model including SAE1 and PLK1. These results might be important for better understanding of the role of SAE1 in TNBC. In addition, DNA methyltransferase and TFs inhibitor treatments targeting SAE1 might improve the survival of TNBC patients.

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Multiple functions of pyruvate kinase M2 in various cell types

Lee

Min

Kim

et al. 2021

Journal Cellular Physiology

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Glucose metabolism is a mechanism by which energy is produced in form of adenosine triphosphate (ATP) by mitochondria and precursor metabolites are supplied to enable the ultimate enrichment of mature metabolites in the cell. Recently, glycolytic enzymes have been shown to have unconventional but important functions. Among these enzymes, pyruvate kinase M2 (PKM2) plays several roles including having conventional metabolic enzyme activity, and also being a transcriptional regulator and a protein kinase. Compared with the closely related PKM1, PKM2 is highly expressed in cancer cells and embryos, whereas PKM1 is dominant in mature, differentiated cells. Posttranslational modifications such as phosphorylation and acetylation of PKM2 change its cellular functions. In particular, PKM2 can translocate to the nucleus, where it regulates the transcription of many target genes. It is notable that PKM2 also acts as a protein kinase to phosphorylate several substrate proteins. Besides cancer cells and embryonic cells, astrocytes also highly express PKM2, which is crucial for lactate production via expression of lactate dehydrogenase A (LDHA), while mature neurons predominantly express PKM1. The lactate produced in cancer cells promotes tumor progress and that in astrocytes can Yoon-Beom Lee and Jung Ki Min contributed equally to this study.

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Increased SUMO-activating enzyme SAE1/UBA2 promotes glycolysis and pathogenic behavior of rheumatoid fibroblast-like synoviocytes

Cited by 33 publications

References 51 publications

Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis

Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis

The Expression and Prognostic Value of SUMO1-Activating Enzyme Subunit 1 and Its Potential Mechanism in Triple-Negative Breast Cancer

Multiple functions of pyruvate kinase M2 in various cell types

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