Abstract

Long non‐coding RNAs (lncRNAs) are critical regulators in cancer. However, the involvement of lncRNAs in TGF‐β‐regulated tumorigenicity is still unclear. Here, we identify TGF‐β‐activated lncRNA LINC00115 as a critical regulator of glioma stem‐like cell (GSC) self‐renewal and tumorigenicity. LINC00115 is upregulated by TGF‐β, 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.