Long Noncoding RNANEAT1, Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/β-Catenin Pathway by Scaffolding EZH2.

Abstract

Purpose: Long noncoding RNAs have been implicated in gliomagenesis, but their mechanisms of action are mainly undocumented. Through public glioma mRNA expression data sets, we found thatNEAT1was a potential oncogene. We systematically analyzed the clinical significance and mechanism ofNEAT1in glioblastoma.Experimental Design:Initially, we evaluated whetherNEAT1expression levels could be regulated by EGFR pathway activity. We subsequently evaluated the effect ofNEAT1on the WNT/β-catenin pathway and its target binding gene. The animal model supported the experimental findings.Results:We found thatNEAT1levels were regulated by EGFR pathway activity, which was mediated by STAT3 and NFκB (p65) downstream of the EGFR pathway. Moreover, we found thatNEAT1was critical for glioma cell growth and invasion by increasing β-catenin nuclear transport and downregulating ICAT, GSK3B, and Axin2. Taken together, we found thatNEAT1could bind to EZH2 and mediate the trimethylation of H3K27 in their promoters.NEAT1depletion also inhibited GBM cell growth and invasion in the intracranial animal model.Conclusions:The EGFR/NEAT1/EZH2/β-catenin axis serves as a critical effector of tumorigenesis and progression, suggesting new therapeutic directions in glioblastoma.Clin Cancer Res; 24(3); 684-95. ©2017 AACR.