MicroRNA-101 Exerts Tumor-Suppressive Functions In Non-small Cell Lung Cancer Through Directly Targeting Enhancer Of Zeste Homolog 2 (EZH2)

Purpose:Overexpression of the enhancer of zeste homolog 2 (EZH2) protein has been found in broad range of cancer types, including non small cell lung cancer (NSCLC). However, the mechanisms by which EZH2 becomes over-expressed in NSCLC remain unclear. microRNAs (miRNAs) can regulate target gene expression through translational control. With the present study we investigated whether microRNA (miR-101) regulates EZH2 expression in NSCLC.Methods:We evaluated the expression of miR-101 and EZH2 in 20 matched NSCLC and adjacent non-tumor lung tissues by qRT-PCR and Immunohistochemistry, respectively. Luciferase reporter assay was used to determine whether miR-101 directly targets EZH2. To assess the effect of miR-101 on NSCLC biological behavior, cell proliferation, invasion and response to chemotherapy were analyzed using NSCLC cells transfected with miR-101 mimics or transfected with specific siRNA to deplete EZH2 (siRNA-EZH2).Results:Reduced expression of miR-101 is associated with overxpression of EZH2 in NSCLC tumor tissues. Transfection of miR-101 mimics significantly suppressed the activity of the luciferase reporter containing wild type but not mutant EZH2 3'-UTR and decreased EZH2 mRNA and protein levels in NSCLC cell lines. Furthermore, enforced expression of miR-101 or knockdown of EZH2 led to reduced NSCLC cell proliferation and invasion and sensitized cancer cells to paclitaxel (PTX)-mediated apoptosis through inducing expression of the pro-apoptotic protein Bim.Conclusions:miR-101 inhibits cell proliferation and invasion and enhances PTX-induced apoptosis in NSCLC cells, at least in part, by directly repressing EZH2 expression. Therapeutic strategies to rescue miR-101 expression or slience EZH2 may be beneficial to patients with NSCLC in the future.