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 has a key role in promoting cell survival. Here we perform a genome-wide RNAi screen to identify transcriptional regulators of ATF5. Our results reveal an essential survival pathway in malignant glioma, whereby activation of a RAS-mitogen-activated protein kinase or phosphoinositide-3-kinase signaling cascade leads to induction of the transcription factor cAMP response element-binding protein-3-like-2 (CREB3L2), which directly activates ATF5 expression. ATF5, in turn, promotes survival by stimulating transcription of myeloid cell leukemia sequence-1 (MCL1), an antiapoptotic B cell leukemia-2 family member. Analysis of human malignant glioma samples indicates that ATF5 expression inversely correlates with disease prognosis. The RAF kinase inhibitor sorafenib suppresses ATF5 expression in glioma stem cells and inhibits malignant glioma growth in cell culture and mouse models. Our results demonstrate that ATF5 is essential in malignant glioma genesis and reveal that the ATF5-mediated survival pathway described here provides potential therapeutic targets for treatment of malignant glioma.
Sheng
Zhi
Z
Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Li
Li
L
Zhu
Lihua J
LJ
Smith
Thomas W
TW
Demers
Andrea
A
Ross
Alonzo H
AH
Moser
Richard P
RP
Green
Michael R
MR
D051696:Activating Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001557:Benzenesulfonates / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000502:physiology; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D000077157:Sorafenib; D014407:Tumor Cells, Cultured
D051696:Activating Transcription Factors; C471855:Atf5 protein, mouse; D001557:Benzenesulfonates; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib