c-Src facilitates tumorigenesis by phosphorylating and activating G6PD

Ma, Huanhuan; Zhang, Fengqiong; Zhou, Lin; Cao, Tingyan; Sun, Dao Heng; Wen, Shixiong; Zhu, Jinpei; Xiong, Zhaoqianyu; Tsau, Ming-Tong; Cheng, Mei‐Ling; Hung, Li-Man; Zhou, Yanming; Li, Qinxi

doi:10.1038/s41388-021-01673-0

Cited by 20 publications

(19 citation statements)

References 34 publications

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“…G6PD overactivation in tumor cells is regulated at the transcriptional or posttranslational level ( 17 , 21 , 22 , 27 – 29 ). As shown in Figure 3B , the expression of G6PD remains unchanged in Pol ι differentially expressed cells, suggesting that posttranslational modification may be responsible for G6PD activation, such as OGT induced O-GlcNAcylation ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

“…Glucose-6-phosphate dehydrogenase (G6PD) serves as a pacemaker of PPP due to its activity to shunt glucose flux to PPP and catalyze the first and rate-limiting step of PPP (17). Mounting evidence indicated that increased glucose flux towards PPP and overactivation of G6PD are common in many cancer types, including clear cell renal cell carcinoma, hepatocellular carcinoma, colorectal cancer, prostate cancer, and ESCC (23)(24)(25)(26)(27). It is known that G6PD overactivation in tumor cells is regulated at the transcriptional or posttranslational level (17,21,22,(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

“…Mounting evidence indicated that increased glucose flux towards PPP and overactivation of G6PD are common in many cancer types, including clear cell renal cell carcinoma, hepatocellular carcinoma, colorectal cancer, prostate cancer, and ESCC (23)(24)(25)(26)(27). It is known that G6PD overactivation in tumor cells is regulated at the transcriptional or posttranslational level (17,21,22,(27)(28)(29). Recent evidence suggested that OGT promotes O-GlcNAcylation of G6PD, and this process is critical for G6PD activation and tumor progression (30).…”

Section: Introductionmentioning

confidence: 99%

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DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation

Gao

et al. 2021

Front. Oncol.

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Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers with rapid progression and a high mortality rate. Our previous study demonstrated that DNA polymerase iota (Pol ι) is overexpressed in ESCC tumors and correlates with poor prognosis. However, its role in ESCC proliferation remains obscure. We report here that Pol ι promotes ESCC proliferation and progression through Erk- O-GlcNAc transferase (OGT) regulated Glucose-6-phosphate dehydrogenase (G6PD) overactivation. Cell clonogenic ability was assessed by colony formation assay. Cell proliferation was assessed by EdU incorporation assay. Our transcriptome data was reanalyzed by GSEA and validated by analysis of cellular metabolism, G6PD activity, and cellular NADPH concentration. The level of Pol ι, OGT, G6PD and O-GlcNAcylation in ESCC cells and patient samples were analyzed. The MEK inhibitor PD98059 was applied to confirm OGT expression regulation by the Erk signaling. The G6PD inhibitor polydatin was used to examine the role of G6PD activation in Pol ι promoted proliferation. We found that Pol ι promotes ESCC proliferation. It shunted the glucose flux towards the pentose phosphate pathway (PPP) by activating G6PD through OGT-promoted O-GlcNAcylation. The expression of OGT was positively correlated with Pol ι expression and O-GlcNAcylation. Notably, elevated O-GlcNAcylation was correlated with poor prognosis in ESCC patients. Pol ι was shown to stimulate Erk signaling to enhance OGT expression, and the G6PD inhibitor polydatin attenuated Pol ι induced tumor growth in vitro and in vivo. In conclusion, Pol ι activates G6PD through Erk-OGT-induced O-GlcNAcylation to promote the proliferation and progression of ESCC, supporting the notion that Pol ι is a potential biomarker and therapeutic target of ESCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation

Gao

et al. 2021

Front. Oncol.

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“…Several tyrosine sites of G6PD can be phosphorylated by Src, Frontiers in Pharmacology frontiersin.org including Y112, Y428, and Y507. Among them, Y112 is considered to be the most important phosphorylation site of Src and phosphorylation at this site increases the enzymatic activity of G6PD and enhances PPP flow to promote tumorigenesis (Pan et al, 2009;Ma et al, 2021). Other members of the Src family can also directly bind phosphorylated G6PD.…”

Section: Post-translational Modification Regulates G6pd Expression In...mentioning

confidence: 99%

“…Lactatemay be employed as a substrate for lactylation modifications to regulate the expression of downstream genes. Lactylation modifications of non-histone proteins may be of great interest for future research, even if no relevant reports are currently available (Sun L. et al, 2021).…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Recent findings in the regulation of G6PD and its role in diseases

et al. 2022

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Glucose-6-phosphate dehydrogenase (G6PD) is the only rate-limiting enzyme in the pentose phosphate pathway (PPP). Rapidly proliferating cells require metabolites from PPP to synthesize ribonucleotides and maintain intracellular redox homeostasis. G6PD expression can be abnormally elevated in a variety of cancers. In addition, G6PD may act as a regulator of viral replication and vascular smooth muscle function. Therefore, G6PD-mediated activation of PPP may promote tumor and non-neoplastic disease progression. Recently, studies have identified post-translational modifications (PTMs) as an important mechanism for regulating G6PD function. Here, we provide a comprehensive review of various PTMs (e.g., phosphorylation, acetylation, glycosylation, ubiquitination, and glutarylation), which are identified in the regulation of G6PD structure, expression and enzymatic activity. In addition, we review signaling pathways that regulate G6PD and evaluate the role of oncogenic signals that lead to the reprogramming of PPP in tumor and non-neoplastic diseases as well as summarize the inhibitors that target G6PD.

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