We report a mechanism of translational control that is determined by a requirement for eIF4A RNA helicase activity and underlies the anticancer effects of Silvestrol and related compounds. Briefly, activation of cap-dependent translation contributes to T-cell leukemia (T-ALL) development and maintenance. Accordingly, inhibition of translation initiation factor eIF4A with Silvestrol produces powerful therapeutic effects against T-ALL in vivo. We used transcriptome-scale ribosome footprinting on Silvestrol-treated T-ALL cells to identify Silvestrol-sensitive transcripts and the hallmark features of eIF4A-dependent translation. These include a long 5 UTR and a 12-mer sequence motif that encodes a guanine quartet (CGG)4. RNA folding algorithms as well as experimental evidences pinpoint the (CGG)4 motif as a common site of RNA G-quadruplex structures within the 5 UTR. In T-ALL these structures mark approximately eighty highly Silvestrol-sensitive transcripts that include key oncogenes and transcription factors and contribute to the drug's anti-leukemic action. Hence, the eIF4A-dependent translation of G-quadruplex containing transcripts emerges as a gene-specific and therapeutically targetable mechanism of translational control.
Citation Format: Kamini Singh, Andrew L. Wolfe, Yi Zhong, Gunnar Rätsch, Hans-Guido Wendel. The 5 UTR of many oncogenes and transcription factors encodes a targetable dependence on the eIF4A RNA helicase. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B23.