N6-methyladenosine (m6A) methyltransferase WTAP accelerates the Warburg effect of gastric cancer through regulating HK2 stability

Yu, Han; Zhao, Kun; Zeng, H.; Li, Zhiwang; Chen, Kai; Zhang, Zhuoxin; Li, En; Wu, Zuguang

doi:10.1016/j.biopha.2020.111075

Cited by 80 publications

(65 citation statements)

References 22 publications

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“…There is evidence that WTAP participates in tumorigenesis and cancer progression [ 30 ]. Recent study also documents that WTAP accelerates glucose metabolism of gastric cancer [ 31 ]. Here our findings highlight the significance of WTAP-mediated m6A methylation in C5aR1 + neutrophil-induced tumor glycolysis, suggesting a critical role of WTAP in tumor metabolism.…”

Section: Discussionmentioning

confidence: 99%

C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1

Liu

Yang

et al. 2021

Cell Death Dis

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Neutrophils are significant compositions of solid tumors and exert distinct functions in different types of tumors. However, the precise role of neutrophils in the progression of breast cancer (BC) is presently unclear. In this study, by investigating the single-cell RNA sequencing data, we identify a new neutrophil subset, C5aR1-positive neutrophils, that correlates with tumor progression and poor survival for BC patients. Furthermore, it is discovered that C5aR1-positive neutrophils enhance BC cell glycolysis via upregulating ENO1 expression. Mechanically, C5aR1-positive neutrophil-secreted IL1β and TNFα cooperatively activate ERK1/2 signaling, which phosphorylates WTAP at serine341 and thereby stabilizes WTAP protein. The stabilization of WTAP further promotes RNA m6A methylation of ENO1, impacting the glycolytic activity of BC cells. Importantly, C5aR1-positive neutrophils also promote breast cancer growth in vivo, and this effect is abolished by WTAP silencing. In clinical BC samples, increased C5aR1-positive neutrophils correlate with elevated IL1β, TNFα, and ENO1 expression. A high co-expression of C5aR1-positive neutrophil gene signature and ENO1 predicts worse prognosis of BC patients compared with a low co-expression. Collectively, our study reveals a novel subset of C5aR1-positive neutrophils that induces breast cancer glycolysis via increasing ERK1/2-WTAP-dependent m6A methylation of ENO1. These findings support the potential for exploration of C5aR1-positive neutrophils as a therapeutic target in breast cancer.

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Section: Discussionmentioning

confidence: 99%

C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1

Liu

Yang

et al. 2021

Cell Death Dis

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“…119 Moreover, WTAP enhances stability of HK2 mRNA by binding with the 3 0 UTR m 6 A site in gastric cancer. 120 Casein kinase 2 (CK2) is associated with glycolysis, and CK2a is an essential catalytic subunit of the holoenzyme. In bladder cancer, ALKBH5 specifically recognizes the m 6 A sites of the 3 0 UTR in CK2a mRNA and reduces its stability, thus inhibiting cell glycolysis and proliferation.…”

Section: Modification Modulates Glycolysis In Cancer Cellsmentioning

confidence: 99%

Regulatory role and mechanism of m6A RNA modification in human metabolic diseases

Zhang¹,

Chen²,

Zheng³

et al. 2021

Molecular Therapy - Oncolytics

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Metabolic diseases caused by disorders in amino acids, glucose, lipid metabolism, and other metabolic risk factors show high incidences in young people, and current treatments are ineffective. N 6 -methyladenosine (m 6 A) RNA modification is a posttranscriptional regulation of gene expression with several effects on physiological processes and biological functions. Recent studies report that m 6 A RNA modification is involved in various metabolic pathways and development of common metabolic diseases, making it a potential disease-specific therapeutic target. This review explores components, mechanisms, and research methods of m 6 A RNA modification. In addition, we summarize the progress of research on m 6 A RNA modification in metabolism-related human diseases, including diabetes, obesity, non-alcoholic fatty liver disease, osteoporosis, and cancer. Furthermore, opportunities and the challenges facing basic research and clinical application of m 6 A RNA modification in metabolism-related human diseases are discussed. This review is meant to enhance our understanding of the molecular mechanisms, research methods, and clinical significance of m 6 A RNA modification in metabolism-related human diseases.

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“…In gastric cancer, glycolytic proficiency negatively affects survival outcomes of metastatic gastric cancer patients treated with paclitaxel-ramucirumab systemic therapy [8]. Notably, several reports have documented the regulators of the Warburg effect in gastric cancer, such as MACC1 [9], FBP1 [10], WTAP [11], and MUC16 [12]. However, the molecular mechanisms underlying the Warburg effect in gastric cancer remain unclear.…”

Section: Ivyspringmentioning

confidence: 99%

CD73 is a hypoxia-responsive gene and promotes the Warburg effect of human gastric cancer cells dependent on its enzyme activity

et al. 2021

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Background:The Warburg effect is closely associated with malignant phenotypes and poor prognosis in gastric cancer. CD73 is a glycosylphosphatidylinositol (GPI) anchored cell surface protein that functions as an oncogene in a variety of human cancers. However, the relationship between CD73 and the Warburg effect has yet to be fully understood. Methods: Integrative analysis was performed to identify glycolysis-related genes in gastric cancer. Loss-of-function and gain-of-function are performed to demonstrate the roles of CD73 in gastric cancer cell proliferation and glycolysis. Cell biological, molecular, and biochemical approaches are used to uncover the underlying mechanism. Results: In this study, we find that CD73 is a glycolysis-associated gene and is induced by hypoxia in gastric cancer. Genetic silencing of CD73 reduces gastric cancer cell proliferation and glycolytic ability. Opposite effects were observed by CD73 overexpression. Importantly, pharmacological inhibition of CD73 activity by APCP inhibits tumor growth, which can be largely compromised by the addition of adenosine, suggesting an enzyme activity-dependent effect of CD73 in gastric cancer. Furthermore, hijacking tumor glycolysis by 2-DG or galactose largely abrogated the oncogenic roles of CD73, indicating that CD73 promotes tumor growth in a glycolysis-dependent manner in gastric cancer. By the subcutaneous xenograft model, we confirmed the promotive roles of CD73 in regulating cell proliferation and glycolysis in gastric cancer. Conclusions: This study provides strong evidence of the involvement of CD73 in the Warburg effect and indicates that it could be a novel antitumor strategy to target tumor metabolism in gastric cancer.

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N6-methyladenosine (m6A) methyltransferase WTAP accelerates the Warburg effect of gastric cancer through regulating HK2 stability

Cited by 80 publications

References 22 publications

C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1

C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1

Regulatory role and mechanism of m6A RNA modification in human metabolic diseases

CD73 is a hypoxia-responsive gene and promotes the Warburg effect of human gastric cancer cells dependent on its enzyme activity

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