METTL3-mediated m⁶A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance

Abstract

ObjectiveN6-methyladenosine (m6A) RNA methylation and its associated methyltransferase METTL3 are involved in tumour initiation and progression via the regulation of RNA function. This study explored the biological function and clinical significance of METTL3 in gastric cancer (GC).DesignThe prognostic value of METTL3 expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human GC cohort. The biological role and mechanism of METTL3 in GC tumour growth and liver metastasis were determined in vitro and in vivo.ResultsThe level of m6A RNA was significantly increased in GC, and METTL3 was the main regulator involved in the abundant m6A RNA modification. METTL3 expression was significantly elevated in GC tissues and associated with poor prognosis. Multivariate Cox regression analysis revealed that METTL3 expression was an independent prognostic factor and effective predictor in human patients with GC. Moreover, METTL3 overexpression promoted GC proliferation and liver metastasis in vitro and in vivo. Mechanistically, P300-mediated H3K27 acetylation activation in the promoter of METTL3 induced METTL3 transcription, which stimulated m6A modification of HDGF mRNA, and the m6A reader IGF2BP3 then directly recognised and bound to the m6A site on HDGF mRNA and enhanced HDGF mRNA stability. Secreted HDGF promoted tumour angiogenesis, while nuclear HDGF activated GLUT4 and ENO2 expression, followed by an increase in glycolysis in GC cells, which was correlated with subsequent tumour growth and liver metastasis.ConclusionsElevated METTL3 expression promotes tumour angiogenesis and glycolysis in GC, indicating that METTL3 expression is a potential prognostic biomarker and therapeutic target for human GC.

High expression of WTAP leads to poor prognosis of gastric cancer by influencing tumour‐associated T lymphocyte infiltration

“…Zhang C et al found that low m6A levels can lead to the proliferation of GC cells, resulting in GC progression . Wang et al studied the related effects of m6A methylation on the prognosis of GC and found that m6A methylation can lead to the progression of GC and can lead to poor prognosis of GC patients . We studied the effect of WTAP on the prognosis of GC and found that high WTAP expression was associated with poor prognosis of patients.…”

m6A-dependent up-regulation of DRG1 by METTL3 and ELAVL1 promotes growth, migration, and colony formation in osteosarcoma

“…m6A reader IGF2BP3 further enhanced HDGF mRNA stability, resulting in increased HDGF expression. HDGF contributed to the proliferation and metastasis of gastric cancer [26]. In addition, YAP and MALAT1 expression was also increased by METTL3 through m6A modification [27].…”

m6A-binding proteins: the emerging crucial performers in epigenetics

“…And IGF2BP1 specially recognized the m 6 A-modified SEC62 mRNA and augmented its expression at both mRNA and protein levels [53]. Furthermore, another member of IGF2BP proteins IGF2BP3 could directly bind to the m 6 A sites of HDGF mRNA and then improved HDGF stability by enhancing the m 6 A-associated mRNA translation [54]. And HDGF has an ability of facilitating tumor angiogenesis.…”

“…Increasing the expression of β-catenin, WNT6 and FZD9A to activate Wnt/β-catenin pathway [49] YTHDF3 GAS5 Enhancing the degradation of lncRNA GAS5 [50] YTHDC1 circNSUN2 Facilitating circNSUN2 export from nucleus to cytoplasm [51] IGF2BP2 HMGA2 Forming a circNSUN2/IGF2BP2 complex to fortify the stability of HMGA2 [51] IGF2BP2 SOX2 Stabilizing SOX2 mRNA [52] Gastric cancer IGF2BP1 SEC62 Augmenting SEC62 mRNA translation [53] IGF2BP3 HDGF Facilitating HDGF mRNA expression [54] HuR ZMYM1 Fortifying the stability of ZMYM1 mRNA [116] Lung cancer YTHDF1 CDK2, CDK4, cyclinD1…”