Abstract
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.
Highlights
Stomach cancer is the fourth most common malignancy in men and the fifth most common malignancy in women[1]
Flow cytometry, and clone formation assays, we found that Methylene tetrahydrofolate reductase (MTHFR) silencing could suppress gastric cancer (GC) cell proliferation and cell cycle G1/S phase transformation and induce cell apoptosis (Fig. 4a–d and Supplementary Fig. S4)
Our findings indicated that miR-22 inhibits GC cell proliferation by directly targeting methyl-CpG-binding protein 2 (MeCP2), MTHFD2, and MTHFR
Summary
Stomach cancer is the fourth most common malignancy in men and the fifth most common malignancy in women[1]. DNA methylation participates in the regulation of gene expression by recruiting methyl-CpG-binding proteins, such as methylated DNA-binding domain (MBD) 1–4 and methyl-CpG-binding protein 2 (MeCP2). 47% of the investigated human miRNAs have been associated with CpG islands, suggesting that miRNAs are subject to transcriptional regulation by DNA methylation[6]. MiR-22, a tumor suppressor gene, is downregulated in a wide variety of tumors, such as colorectal cancer, hepatocellular carcinoma, breast cancer, and lung cancer[7,8,9]. MiR-22 is involved in tumorigenesis by targeting HIF-1α, SIRT1, CDK6, Sp1, HDAC4, MAX, Galectin-9, NET1, PAPST1, ESR1, TIAM1, cyclin A2/. Associating domains (TADs) facilitate the formation of three-dimensional genomic architecture, providing physical contacts
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