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
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.
