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

• Published in: Cell reports (Cambridge) 2021-06, Vol.35 (13), p.109321-109321, Article 109321
• Main Authors: Kuzuoglu-Ozturk, Duygu, Hu, Zhiqiang, Rama, Martina, Devericks, Emily, Weiss, Jacob, Chiang, Gary G., Worland, Stephen T., Brenner, Steven E., Goodarzi, Hani, Gilbert, Luke A., Ruggero, Davide
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions - genetics; Animals; Apoptosis - genetics; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; bcl-X Protein - metabolism; Bcl-xL; cancer; Cell Line, Tumor; Cell Movement; Cell Proliferation; CRISPR-Cas Systems - genetics; CRISPRi; eIF4E; EJC; Eukaryotic Initiation Factor-4E - genetics; Eukaryotic Initiation Factor-4E - metabolism; Exons - genetics; Genetic Testing; Genome, Human; Humans; Male; Metalloendopeptidases - metabolism; Mice; mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - metabolism; Neoplasms - genetics; Neoplasms - pathology; Peptide Hydrolases - metabolism; Protein Biosynthesis - genetics; Signal Transduction - genetics; Stress, Physiological; Tfeb; translation control; UPRmt-like stress response
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109321

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. [Display omitted] •Genome-wide CRISPRi screen reveals more than 600 synthetic lethal partners of eIF4E•Functional interaction between eIF4E and Bcl-xL is important for tumor growth•Mitochondrial dysfunction triggers an eIF4E-dependent adaptive stress response•Interaction between eIF4E and EJC controls the migratory capacity of cancer cells Kuzuoglu-Ozturk et al. identify more than 600 genetic interactions that sustain oncogenic activity of the major cap-binding protein eIF4E by a genome-wide CRIPSRi screen. Their data reveal interactions among distinct cellular processes and eIF4E, uncovering several cancer-specific vulnerabilities.