DNA methylation-induced ablation of miR-133a accelerates cancer aggressiveness in glioma through upregulating peroxisome proliferator-activated receptor γ.

Abstract

Emerging evidences suggest that miRNAs can be used as theranostic biomarkers for multiple cancers, including glioma. Thus, identification of novel miRNAs for glioma treatment and prognosis becomes necessary and urgent. Here, by analyzing miRNA expression profiles in the glioma and para-cancer tissues by miRNA microarray and verified by RT-PCR, we found that miR-133a was significantly downregulated in the cancerous tissues, and patients with low-expressed miR-133a levels predicted an unfavorable prognosis. The following functional experiments confirmed that overexpression of miR-133a restrained cell proliferation and colony formation abilities, and induced cell cycle arrest to restrain cancer progression in glioma cells. Then, the underlying mechanisms were uncovered, and the peroxisome proliferator-activated receptor γ (PPARγ, PPARG) was verified as the downstream target of miR-133a. Mechanistically, miR-133a negatively regulated PPARG expressions by binding to its 3' untranslated regions (3'UTR). The following rescuing experiments evidenced that miR-133a overexpression-induced anti-cancer effects in glioma cells were abrogated by upregulating PPARγ. Interestingly, we noticed that the promoter region of miR-133a was hypermethylated, and removal of DNA methylation by 5-Azacytidine (AZA) significantly increased the expression levels of miR-133a in glioma cells. Taken together, we concluded that DNA-methylation-induced miR-133a silence contributed to cancer progression in glioma through upregulating PPARγ, and firstly identified the DNA-methylation-regulated miR-133a/PPARG axis as the novel indicators for glioma treatment and prognosis.