MiR-129 triggers autophagic flux by regulating a novel Notch-1/ E2F7/Beclin-1 axis to impair the viability of human malignant glioma cells

Abstract

// Xiong Chen 1, * , Yingying Zhang 1, * , Yingying Shi 1 , Haiwei Lian 4 , Huilin Tu 1 , Song Han 1 , Jun Yin 1 , Biwen Peng 1, 2 , Beiyan Zhou 5 , Xiaohua He 1, 2 , Wanhong Liu 1, 3 1 School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China 2 Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China 3 Hubei Province Key Laboratory of Allergy and Immunology, Wuhan 430071, China 4 Department of Neurosurgery, Wuhan University Renmin Hospital, Wuhan 430060, China 5 Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A & M University, Texas 77843, USA * These authors contributed equally to this work Correspondence to: Xiaohua He, e-mail: hexiaohua@whu.edu.cn Wanhong Liu, e-mail: liuwanhong@whu.edu.cn Keywords: miR-129, E2F7, Notch-1, autophagy, glioma Received: July 07, 2015      Accepted: January 01, 2016      Published: January 25, 2016 ABSTRACT Abnormalities of autophagy have been implicated in an increasing number of human cancers, including glioma. To date, there is a wealth of evidence indicating that microRNAs (miRNAs) contribute significantly to autophagy in a variety of cancers. Previous studies have suggested that miR-129 functioned as an important inhibitor of the cell cycle and could promote the apoptosis of many cancer cell lines in vitro . Here, we reported that miR-129 acted as a potent inducer of autophagy. Forced expression of miR-129 could induce autophagic flux by targetedly suppressing Notch-1 in glioma cells. The autophagy induced by miR-129 could restrain the activity of mammalian target of rapamycin (mTOR) and upregulate Beclin-1. Moreover, we demonstrated that E2F transcription factor 7 (E2F7) could also trigger autophagic flux by upregulating Beclin-1 and mediating miR-129-induced autophagy. Additionally, knockdown of Notch-1 could upregulate the expression of E2F7, whereas downregulation of E2F7 alleviated shNotch-1-induced autophagic flux. In particular, knockdown of endogenous Beclin-1 could effectively reduce autophagic flux stimulated by miR-129 and E2F7. Interestingly, upon attenuation of miR-129- or E2F7-triggered autophagic flux rescued cell viability suppressed by them. More importantly, intratumoral injection of pHAGE-miR-129 lentivirus in a nude mouse xenograft model significantly restrained tumor growth and triggered autophagy. In conclusion, these findings identify a new function for miR-129 as a potent inducer of autophagy through a novel Notch-1/E2F7/Beclin-1 axis in glioma.