miR-137 is a tumor suppressor in endometrial cancer and is repressed by DNA hypermethylation. Lab Invest 2018 Nov;98(11):1397-1407
Date
06/30/2018Pubmed ID
29955087Pubmed Central ID
PMC6214735DOI
10.1038/s41374-018-0092-xScopus ID
2-s2.0-85049129398 (requires institutional sign-in at Scopus site) 58 CitationsAbstract
Endometrial cancer is the most common gynecological cancer in the United States. We wanted to identify epigenetic aberrations involving microRNAs (miRNAs), whose genes become hypermethylated in endometrial primary tumors. By integrating known miRNA sequences from the miRNA database (miRBase) with DNA methylation data from methyl-CpG-capture sequencing, we identified 111 differentially methylated regions (DMRs) associated with CpG islands (CGIs) and miRNAs. Among them, 22 DMRs related to 29 miRNAs and within 8 kb of CGIs were hypermethylated in endometrial tumors but not in normal endometrium. miR-137 was further validated in additional endometrial primary tumors. Hypermethylation of miR-137 was found in both endometrioid and serous endometrial cancer (P < 0.01), and it led to the loss of miR-137 expression. Treating hypermethylated endometrial cancer cells with epigenetic inhibitors reactivated miR-137. Moreover, genetic overexpression of miR-137 suppressed cancer cell proliferation and colony formation in vitro. When transfected cancer cells were implanted into nude mice, the cells that overexpressed miR-137 grew more slowly and formed smaller tumors (P < 0.05) than vector transfectants. Histologically, xenograft tumors from cancer cells expressing miR-137 were less proliferative (P < 0.05), partly due to inhibition of EZH2 and LSD1 expression (P < 0.01) in both the transfected cancer cells and tumors. Reporter assays indicated that miR-137 targets EZH2 and LSD1. These results suggest that miR-137 is a tumor suppressor that is repressed in endometrial cancer because the promoter of its gene becomes hypermethylated.
Author List
Zhang W, Chen JH, Shan T, Aguilera-Barrantes I, Wang LS, Huang TH, Rader JS, Sheng X, Huang YWAuthor
Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenocarcinomaAnimals
Cell Line, Tumor
DNA Methylation
Endometrial Neoplasms
Enhancer of Zeste Homolog 2 Protein
Female
Gene Silencing
Histone Demethylases
Humans
Mice, Nude
MicroRNAs