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

• DOI: 10.1016/j.celrep.2021.109321
• Publication Date: 2021-06-29T14:37:54Z
• Authors: Duygu Kuzuoglu-Oz...; Zhiqiang Hu; Martina Rama; Emily Devericks; Jacob Weiss; Gary G. Chiang; Stephen T. Worland; Steven E. Brenner; Hani Goodarzi; Luke A. Gilbert; Davide Ruggero
• Keywords: translation control; Male; Tfeb; Medical Physiology; Apoptosis; Mice; Cell Movement; Neoplasms; 2.1 Biological and endogenous factors; Aetiology; Biology (General); Cancer; Pmpcb; 0303 health sciences; Tumor; Genome; UPRmt-like stress response; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Metalloendopeptidases; mitochondrial UPR; Exons; Biological Sciences; Mitochondria; 3. Good health; mitochondria; Biological sciences; EJC; Human; Signal Transduction; 570; autophagy; QH301-705.5; 1.1 Normal biological development and functioning; Physiological; bcl-X Protein; 610; Stress; UPR(mt)-like stress response; Article; Cell Line; Mitochondrial Proteins; 03 medical and health sciences; Underpinning research; Cell Line, Tumor; Genetics; Autophagy; cancer; Animals; Humans; Genetic Testing; Cell Proliferation; Bcl-xL; Genome, Human; CRISPRi; Eukaryotic Initiation Factor-4E; Protein Biosynthesis; eIF4E; Biochemistry and Cell Biology; Generic health relevance; CRISPR-Cas Systems; 5' Untranslated Regions; Peptide Hydrolases

The major cap-binding protein eukaryotic translation initiation factor 4E (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. In this study, we carry out a genome-wide CRISPRi screen wherein we identify more than 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), which is involved in many steps of RNA metabolism, interact to control the migratory properties of cancer cells. Overall, we uncover several cancer-specific vulnerabilities that provide further resolution of the cancer translatome.