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Revealing new molecular pathways for cancer cell fitness through a genetic screen of the cancer translatome

ABSTRACT: The major cap binding protein eIF4E, an ancient protein required for translation of all eukaryotic genomes, is a surprising yet potent oncogenic driver. The genetic interactions that maintain the oncogenic activity of this key translation factor remain unknown. Here we carried out a genome-wide CRISPRi screen wherein we identified over 600 genetic interactions that sustain eIF4E oncogenic activity. Our data show that eIF4E controls the translation of Tfeb, a key executer of the autophagy response. This autophagy survival response is triggered by mitochondrial proteotoxic stress, which allows cancer cell survival. Our screen also reveals a functional interaction between eIF4E and a single anti-apoptotic factor, Bcl-xL, in tumor growth. Furthermore, we show that eIF4E and the exon-junction complex (EJC), involved in many steps of RNA metabolism, interact to control the migratory properties of cancer cells. Overall, we have uncovered several cancer-specific vulnerabilities that provide unprecedented resolution of the cancer translatome.

ORGANISM(S): Mus musculus

PROVIDER: GSE175417 | GEO | 2021/05/25

REPOSITORIES: GEO

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Project description:Accumulating data indicate translation plays a role in cancer biology, particularly its rate limiting stage of initiation. Despite this evolving recognition, the function and importance of specific translation initiation factors is unresolved. The eukaryotic translation initiation complex eIF4F consists of eIF4E and eIF4G at a 1:1 ratio. Although it is expected that they display interdependent functions, several publications suggest independent mechanisms. This study is the first to directly assess the relative contribution of eIF4F components to the expressed cellular proteome, transcription factors, microRNAs, and phenotype in a malignancy known for extensive protein synthesis- multiple myeloma (MM). Previously, we have shown that eIF4E/eIF4GI attenuation (siRNA/ Avastin) deleteriously affected MM cells' fate and reduced levels of eIF4E/eIF4GI established targets. Here, we demonstrated that eIF4E/eIF4GI indeed have individual influences on cell proteome. We used an objective, high throughput assay of mRNA microarrays to examine the significance of eIF4E/eIF4GI silencing to several cellular facets such as transcription factors, microRNAs and phenotype. We showed different imprints for eIF4E and eIF4GI in all assayed aspects. These results promote our understanding of the relative contribution and importance of eIF4E and eIF4GI to the malignant phenotype and shed light on their function in eIF4F translation initiation complex. This study concentrated on a particular cancer model and studied the role of eIF4E and eIF4GI in the design of the cells' proteome. We used an unbiased, high throughput system to evaluate the individual importance of eIF4E and eIF4GI levels in MM. We used models of eIF4E or eIF4GI knocked down (KD) MM cell line RPMI 8226 and profiled their respective translated transcription factors (TF), often tumor suppressors or oncogenes. Furthermore, we assessed the KDs' microRNAs repertoires and cells' phenotype. Significant differences were observed between eIF4E and eIF4GI knockdown imprints.

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Revealing new molecular pathways for cancer cell fitness through a genetic screen of the cancer translatome

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