miR-137 is a tumor suppressor in endometrial cancer and is repressed by DNA hypermethylation

Abstract

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.

A NOTCH1/LSD1/BMP2 Co-Regulatory Network Mediated by miR-137 Negatively Regulates Osteogenesis of Human Adipose-Derived Stem Cells

“…Interestingly, our former research con rmed a positive role of miR-137 in LSD1 expression, which was contrary to several studies reporting that miR-137 directly binds to LSD1 [23,26,51,52]. The contradicted outcomes might be associated with the various biological features of different cell types, and we deduced that there probably exist intermediary regulators working between miR-137 and LSD1 during the osteogenesis of hASCs.…”

MicroRNA‑873 inhibits the proliferation and invasion of endometrial cancer cells by directly targeting hepatoma‑derived growth factor

“…An understanding of the miRNAs associated with EC initiation and progression is crucial for the development of improved therapeutic techniques. Previous studies have demonstrated that numerous miRNAs are associated with EC (27)(28)(29). In the current study, to the best of our knowledge, expression status, functions and governing molecular mechanisms of miR-873 in EC were detected for the first time.…”

miR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4

“…In cancer, miR-137 is often downregulated due to hypermethylation of its CpG island 28 . miR-137 hypermethylation leads to its inhibition in many tumors, such as colorectal cancer, pancreatic cancer, and endometrial cancer [29][30][31] . Functional analysis has indicated that miR-137 can inhibit cell proliferation, cell cycle arrest and apoptosis, cell migration and invasion, and affect chemoresistance [32][33][34][35][36] .…”