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METTL3-mediated m6A methylation of SPHK2 promotes gastric cancer progression by targeting KLF2

Abstract

N6-methyladenosine (m6A) RNA methylation is profoundly involved in epigenetic regulation, especially for carcinogenesis and tumor progression. Mounting evidence suggests that methyltransferase METTL3 regulates malignant behaviors of gastric cancer (GC). However, the clinical significance and biological implication of SPHK2 and its related m6A modification in GC remain unclear. In this study, quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry were utilized to detect the expression profiles and prognostic significance of SPHK2 in GC. Here, we showed that increased SPHK2 was signified a poor prognosis of GC patients. Phosphorylation and ubiquitination assays were used to investigate the possible mechanisms of SPHK2-mediated KLF2 expression. SPHK2 can promote the phosphorylation of KLF2, which triggers the ubiquitination and degradation of KLF2 protein in GC. Methylated RNA immunoprecipitation (MeRIP) was performed to uncover the m6A modification of SPHK2 mRNA. METTL3 promotes translation of SPHK2 mRNA via an m6A-YTHDF1-dependent manner. Functionally, SPHK2 facilitates GC cell proliferation, migration and invasion by inhibiting KLF2 expression. SPHK2/KLF2 regulates the cell proliferation, migration, and invasion induced by METTL3 in GC. Overall, our findings reveal that METTL3-mediated m6A modification of SPHK2 contributes to GC progression, which extends the understanding of the importance m6A methylation in GC and represents a potential target for GC therapy.

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Fig. 1: Upregulated SPHK2 is associated with poor prognosis of GC patients.
Fig. 2: Effects of SPHK2 on the proliferation, migration and invasion of GC cells.
Fig. 3: SPHK2 regulates the degradation of KLF2 in GC cells.
Fig. 4: SPHK2-mediated KLF2 phosphorylation triggers KLF2 destruction in GC cells.
Fig. 5: METTL3 promotes SPHK2 expression by an m6A-YTHDF1-dependent manner in GC cells.
Fig. 6: METTL3/SPHK2/KLF2 axis promotes GC cell proliferation, migration, and invasion.

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Correspondence to Jie Mou.

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Huo, FC., Zhu, ZM., Zhu, WT. et al. METTL3-mediated m6A methylation of SPHK2 promotes gastric cancer progression by targeting KLF2. Oncogene 40, 2968–2981 (2021). https://doi.org/10.1038/s41388-021-01753-1

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