A genome-wide RNA interference screen reveals an essential CREB3L2/ATF5/MCL1 survival pathway in malignant glioma with therapeutic implications

Activating transcription factor 5 (ATF5) is highly expressed in malignant glioma and plays an important role in promoting cell survival. Here we perform a genome-wide RNA interference (RNAi) screen to identify transcriptional regulators of ATF5. Our results reveal an essential survival pathway in malignant glioma, whereby activation of a RAS/MAPK or PI3K signaling cascade leads to induction of the transcription factor CREB3L2, which directly activates ATF5 expression. ATF5, in turn, promotes survival by stimulating transcription of MCL1, an anti-apoptotic BCL2 family member. Analysis of human malignant glioma samples indicates that ATF5 expression inversely correlates with disease prognosis. The RAF inhibitor sorafenib suppresses ATF5 expression in glioma stem cells and inhibits malignant glioma growth in cell culture and mouse xenografts. Our results demonstrate that ATF5 plays an essential role in malignant glioma genesis, and reveal that the ATF5-mediated survival pathway described here provides potential therapeutic targets for treatment of malignant glioma.