Long Noncoding RNA <i>NEAT1</i> , Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/ <b>β</b> -Catenin Pathway by Scaffolding EZH2

<b>Purpose:</b> 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 that <i>NEAT1</i> was a potential oncogene. We systematically analyzed the clinical significance and mechanism of <i>NEAT1</i> in glioblastoma.<b>Experimental Design:</b> Initially, we evaluated whether <i>NEAT1</i> expression levels could be regulated by EGFR pathway activity. We subsequently evaluated the effect of <i>NEAT1</i> on the WNT/β-catenin pathway and its target binding gene. The animal model supported the experimental findings.<b>Results:</b> We found that <i>NEAT1</i> levels were regulated by EGFR pathway activity, which was mediated by STAT3 and NFκB (p65) downstream of the EGFR pathway. Moreover, we found that <i>NEAT1</i> was critical for glioma cell growth and invasion by increasing β-catenin nuclear transport and downregulating ICAT, GSK3B, and Axin2. Taken together, we found that <i>NEAT1</i> could bind to EZH2 and mediate the trimethylation of H3K27 in their promoters. <i>NEAT1</i> depletion also inhibited GBM cell growth and invasion in the intracranial animal model.<b>Conclusions:</b> The EGFR/<i>NEAT1</i>/EZH2/β-catenin axis serves as a critical effector of tumorigenesis and progression, suggesting new therapeutic directions in glioblastoma. <i>Clin Cancer Res; 24(3); 684-95. ©2017 AACR</i>.