This study investigated the effect of methyl-CpG-binding protein 2 (MeCP2) on miRNA transcription. Our results of miRNA chip assay and ChIP-seq showed that MeCP2 inhibited the expressions of numerous miRNAs by binding to their upstream elements, including not only the promoter but also the distal enhancer. Among the affected miRNAs, miR-22 was identified to remarkably suppress gastric cancer (GC) cell proliferation, arrest G1–S cell cycle transition, and induce cell apoptosis by targeting MeCP2, MTHFD2, and MTHFR. Understanding GC metabolism characteristics is the key to developing novel therapies that target GC metabolic pathways. Our study revealed that the metabolic profiles in GC tissues were altered. SAM (S-adenosylmethionine), a universal methyl donor for histone and DNA methylation, which is specifically involved in the epigenetic maintenance of cancer cells, was found increased. The production of SAM is promoted by the folate cycle. Knockdown of MTHFD2 and MTHFR, two key enzymes in folate metabolism and methyl donor SAM production, significantly suppressed GC cell proliferation. MiR-22 overexpression reduced the level of endogenous SAM by suppressing MTHFD2 and MTHFR, inducing P16, PTEN, and RASSF1A hypomethylation. In conclusion, our study suggests that miR-22 was inhibited by MeCP2, resulting in deficiency of endogenous SAM, and ultimately leading to tumor suppressor dysregulation.

本研究调查了甲基 CpG 结合蛋白 2 (MeCP2) 对 miRNA 转录的影响。我们的 miRNA 芯片测定和 ChIP-seq 的结果表明，MeCP2通过结合多种 miRNA 的上游元件（不仅包括启动子，还包括远端增强子）来抑制其表达。在受影响的 miRNA 中，miR-22通过靶向MeCP2、MTHFD2和MTHFR显着抑制胃癌 (GC) 细胞增殖、阻止 G1-S 细胞周期转变并诱导细胞凋亡。了解GC代谢特征是开发针对GC代谢途径的新疗法的关键。我们的研究表明GC组织的代谢谱发生了改变。SAM（S-腺苷甲硫氨酸）是组蛋白和 DNA 甲基化的通用甲基供体，特别参与癌细胞的表观遗传维持，其含量有所增加。叶酸循环促进 SAM 的产生。叶酸代谢和甲基供体 SAM 生成中的两种关键酶MTHFD2和MTHFR的敲低可显着抑制 GC 细胞增殖。MiR-22过表达通过抑制MTHFD2和MTHFR降低内源 SAM 水平，诱导P16、PTEN和RASSF1A低甲基化。总之，我们的研究表明miR-22被 MeCP2 抑制，导致内源性 SAM 缺乏，最终导致抑癌基因失调。