Article ; Online: Revealing molecular pathways for cancer cell fitness through a genetic screen of the cancer translatome.
2021 Volume 35, Issue 13, Page(s) 109321
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | 5' Untranslated Regions/genetics ; Animals ; Apoptosis/genetics ; Autophagy ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; CRISPR-Cas Systems/genetics ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Eukaryotic Initiation Factor-4E/genetics ; Eukaryotic Initiation Factor-4E/metabolism ; Exons/genetics ; Genetic Testing ; Genome, Human ; Humans ; Male ; Metalloendopeptidases/metabolism ; Mice ; Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Neoplasms/genetics ; Neoplasms/pathology ; Peptide Hydrolases/metabolism ; Protein Biosynthesis/genetics ; Signal Transduction/genetics ; Stress, Physiological ; bcl-X Protein/metabolism |
| Chemical Substances | 5' Untranslated Regions ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Eukaryotic Initiation Factor-4E ; Mitochondrial Proteins ; TFEB protein, human ; bcl-X Protein ; Peptide Hydrolases (EC 3.4.-) ; Metalloendopeptidases (EC 3.4.24.-) ; PMPCB protein, human (EC 3.4.24.-) |
| Language | English |
| Publishing date | 2021-06-30 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2649101-1 |
| ISSN | 2211-1247 ; 2211-1247 |
| ISSN (online) | 2211-1247 |
| ISSN | 2211-1247 |
| DOI | 10.1016/j.celrep.2021.109321 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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