TGF‐β‐activated lncRNA LINC00115 is a critical regulator of glioma stem‐like cell tumorigenicity

Long non-coding RNAs (lncRNAs) are critical regulators in cancer. However, the involvement of lncRNAs in TGF-beta-regulated tumorigenicity is still unclear. Here, we identify TGF-beta-activated lncRNA LINC00115 as a critical regulator of glioma stem-like cell (GSC) self-renewal and tumorigenicity. LINC00115 is upregulated by TGF-beta, acts as a miRNA sponge, and upregulates ZEB1 by competitively binding of miR-200s, thereby enhancing ZEB1 signaling and GSC self-renewal. LINC00115 also promotes ZNF596 transcription by preventing binding of miR-200s to the 5'-UTR of ZNF596, resulting in augmented ZNF596/EZH2/STAT3 signaling and GBM tumor growth. Inhibition of EZH2 by genetic approaches or a small molecular inhibitor markedly suppresses LINC00115-driven GSC self-renewal and tumorigenicity. Moreover, LINC00115 is highly expressed in GBM, and LINC00115 expression or correlated co-expression with ZEB1 or ZNF596 is prognostic for clinical GBM survival. Our work defines a critical role of LINC00115 in GSC self-renewal and tumorigenicity, and suggests LINC00115 as a potential target for GBM treatment.