TRANSCRIPTIONAL REGULATION OF ONCOMIR-138 IN MALIGNANT GLIOMAS

Abstract

There are compelling evidences suggesting that aberrant expression of miRNAs is linked to the initiation and progression of malignant gliomas. Recurrence of gliomas have been ascribed to a therapy-resistant subpopulation of glioma stem cells (GSCs). We previously identified microRNA-138 (miR-138) as a prosurvival oncomiR expressed by GSCs. Sequence-specific inhibition of miR-138 prevented tumorsphere formation in vitro and impeded tumorigenesis in vivo. However, the precise molecular mechanism regulating miR-138 transcription in glioma remains unexplored. Here we report the identification of the transcription factor C/EBPβ as a critical regulator of miR-138 expression. We define the function of a unique C/EBPβ binding site embedded in the DNA sequence encoding for miR-138 primary precursor. Knockdown of C/EBPβ prevents tumor growth in vivo by decreasing miR-138 expression. Further dissecting the molecular pathway, we finally demonstrate that C/EBPβ direct interaction with RNA Pol-III complex mediates transcription of oncomiR-138 and other small non-coding RNAs in malignant gliomas.