Hsa_circ_0040809 regulates colorectal cancer development by upregulating methyltransferase DNMT1 via targeting miR-515-5p.

Abstract

Circular RNAs (circRNAs) are key regulators in the progression of various cancers. Abnormal DNA methylation patterns feature prominently in the regulation of the expression of tumor-related genes. This study is aimed at investigating the molecular mechanism of circ_0040809 affecting colorectal cancer (CRC) progression by regulating DNA methyltransferase 1 (DNMT1). circ_0040809 was selected from the circRNA microarray datasets (GSE142837 and GSE138589). Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to examine the expression of circ_0040809, miR-515-5p, and DNMT1 mRNA in paired cancerous and paracancerous tissues of 40 CRC patients, as well as in cell lines. Western blotting was conducted for detecting DNMT1 protein expression in CRC cells. Cell proliferation, migration, and apoptosis were assessed through CCK-8, Transwell, and flow cytometry assays. Bioinformatics and dual-luciferase gene assay were conducted to predict and verify, respectively, the targeted relationships between circ_0040809 and miR-515-5p, as well as between miR-515-5p and DNMT1 mRNA. In CRC tissues and cells, circ_0040809 and DNMT1 expression are markedly increased, whereas miR-515-5p expression is decreased. Also, high circ_0040809 expression is significantly linked to shorter overall survival. Cell function compensation experiments reveal that circ_0040809 silencing inhibits CRC cell proliferation and migration and promotes apoptosis, while circ_0040809 overexpression has the opposite effects. Mechanistically, circ_0040809 competitively binds to miR-515-5p to elevate DNMT1 expression. Rescue assay reveals that overexpressed miR-515-5p partly counteracts the tumor-facilitating impact of circ_0040809. circ_0040809 facilitates CRC cell proliferation and migration, and inhibits apoptosis, through modulating miR-515-5p/DNMT1 axis. Our study implies that targeting circ_0040809 may be a therapy strategy for CRC treatment.