METTL3-mediated m6A methylation of SPHK2 promotes gastric cancer progression by targeting KLF2
METTL3-mediated m6A methylation of SPHK2 promotes gastric cancer progression by targeting KLF2
复制标题
METTL3介导的SPHK2 m6A甲基化通过靶向KLF2促进胃癌进展
DOI：
10.1038/s41388-021-01753-1
复制
发表时间：
2021-03-23
期刊：
影响因子：
8
通讯作者：
Mou, Jie
中科院分区：
文献类型：
--
作者：
Huo, Fu-Chun;Zhu, Zhi-Man;Mou, Jie
N6-甲基腺苷（m（6）A）RNA甲基化在表观遗传调控中有着重要作用，尤其是在肿瘤发生和发展中。越来越多的证据表明，甲基转移酶胃L3调节胃癌（GC）的恶性行为。然而，SPHK 2及其相关m（6）A修饰在胃癌中的临床意义和生物学意义尚不清楚。本研究采用实时荧光定量PCR（qRT-PCR）、免疫印迹和免疫组化方法检测SPHK 2在胃癌中的表达情况，并探讨其与胃癌预后的关系。在这里，我们发现SPHK 2的增加意味着GC患者的预后不良。磷酸化和泛素化分析被用来研究SPHK 2介导的KLF 2表达的可能机制。SPHK 2可以促进KLF 2的磷酸化，从而引发KLF 2蛋白在GC中的泛素化和降解。用甲基化RNA免疫沉淀法（MeRIP）检测SPHK 2 mRNA的m（6）A修饰。胃L3通过m（6）A-YTHDF 1依赖的方式促进SPHK 2 mRNA的翻译。SPHK 2在功能上通过抑制KLF 2表达促进GC细胞增殖、迁移和侵袭。SPHK 2/KLF 2调节胃癌中胃L3诱导的细胞增殖、迁移和侵袭。总之，我们的研究结果表明，胃L3介导的SPHK 2的m（6）A修饰有助于GC进展，这扩展了对GC中m（6）A甲基化重要性的理解，并代表了GC治疗的潜在靶点。
N6-methyladenosine (m(6)A) 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 m(6)A 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 m(6)A modification of SPHK2 mRNA. METTL3 promotes translation of SPHK2 mRNA via an m(6)A-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 m(6)A modification of SPHK2 contributes to GC progression, which extends the understanding of the importance m(6)A methylation in GC and represents a potential target for GC therapy.