EMBR-20. ELONGATION CONTROL OF MRNA TRANSLATION DRIVES GROUP 3 MEDULLOBLASTOMA

Abstract

Medulloblastoma (MB) is the most common pediatric intracranial tumor and leading cause of childhood related cancer deaths. Group 3 affiliation and genetic amplifications of the MYC oncogene are predictors of adverse outcome in MB, underscoring a dire need for novel and more effective therapeutic approaches. The let-7 family of small non-coding RNAs (miRNAs) is known to inhibit tumor progression and regulate metabolism by targeting and degrading several cellular mRNAs, including MYC. Indeed, let-7 miRNAs are frequently repressed in several cancer types, including in MYC-driven MB. We previously reported that the mRNA translation elongation regulator eukaryotic Elongation Factor-2 Kinase (eEF2K) is a pivotal mediator of cancer cell adaptation to nutrient deprivation. In the current work, we identified a potential binding site for let-7 miRNAs on the eEF2K 3’ untranslated region (UTR). In addition, eEF2K mRNA and let-7 miRNA expressions negatively correlate in MB, suggesting a potential regulation of the former by the latter. Let-7 miRNAs transfection decreases eEF2K mRNA and protein levels (by ~40–50%). Down-regulation of luciferase activity by let-7 miRNAs is impaired upon mutation of the let-7 binding site on the eEF2K 3’UTR. Inhibition of eEF2K significantly reduces survival of MYC-amplified MB cell lines under nutrient deprivation, altering their mRNA translation rates. Knockout of eEF2K increases survival of MYC-amplified MB xenografts when mice are kept under calorie restricted diets. We conclude that let-7 miRNAs degrade the eEF2K mRNA by binding to its 3’UTR, indicating that let-7 repression in MYC-driven MB is partially responsible for increased eEF2K levels. Moreover, the let-7-eEF2K axis constitutes a critical mechanism for MYC-driven MB adaptation to acute metabolic stress, representing a promising therapeutic target. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs, as eEF2K activity appears critical under metabolic stress conditions.