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

Duygu Kuzuoglu-Ozturk; Zhiqiang Hu; Martina Rama; Emily Devericks; Jacob Weiss; Gary G. Chiang; Stephen T. Worland; Steven E. Brenner; Hani Goodarzi; Luke A. Gilbert; Davide Ruggero

Cell Reports (Jun 2021)

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

Duygu Kuzuoglu-Ozturk,
Zhiqiang Hu,
Martina Rama,
Emily Devericks,
Jacob Weiss,
Gary G. Chiang,
Stephen T. Worland,
Steven E. Brenner,
Hani Goodarzi,
Luke A. Gilbert,
Davide Ruggero

Affiliations

Duygu Kuzuoglu-Ozturk: Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
Zhiqiang Hu: Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Martina Rama: Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
Emily Devericks: Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
Jacob Weiss: Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
Gary G. Chiang: eFFECTOR Therapeutics, San Diego, CA 92121, USA
Stephen T. Worland: eFFECTOR Therapeutics, San Diego, CA 92121, USA
Steven E. Brenner: Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Hani Goodarzi: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics and Department of Urology, University of California, San Francisco, San Francisco CA, 94158, USA
Luke A. Gilbert: Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
Davide Ruggero: Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author

Journal volume & issue: Vol. 35, no. 13
p. 109321

Abstract

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Summary: 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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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