MiR-22, regulated by MeCP2, suppresses gastric cancer cell proliferation by inducing a deficiency in endogenous S-adenosylmethionine

• Published in: Oncogenesis (New York, NY) Vol. 9; no. 11; p. 99
• Main Authors: Tong, Dongdong, Zhang, Jing, Wang, Xiaofei, Li, Qian, Liu, Liying, Lu, Axin, Guo, Bo, Yang, Juan, Ni, Lei, Qin, Hao, Zhao, Lingyu, Huang, Chen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-11-2020; Nature Publishing Group
• Subjects: 101/58; 13/2; 13/31; 13/51; 13/89; 14/1; 14/19; 14/35; 38/1; 38/23; 38/61; 45/44; 631/67/1504/1829; 631/67/2327; 64/60; 82/80; Adenosylmethionine; Apoptosis; Cell Biology; Cell cycle; Cell growth; Cell proliferation; CpG islands; DNA methylation; Epigenetics; Folic acid; Gastric cancer; Guanylate cyclase; Histones; Human Genetics; Internal Medicine; MeCP2 protein; Medicine; Medicine & Public Health; Metabolic pathways; Metabolism; Methyl-CpG binding protein; Methylenetetrahydrofolate reductase; miRNA; Oncology; PTEN protein; S-Adenosylmethionine; Transcription; Tumor suppressor genes
• ISSN: 2157-9024; 2157-9024
• DOI: 10.1038/s41389-020-00281-z

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.