Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3

Yoshinori Tsukumo, Tommy Alain, Bruno D. Fonseca, Robert Nadon and Nahum Sonenberg ()
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Yoshinori Tsukumo: McGill University
Tommy Alain: Microbiology and Immunology, Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa
Bruno D. Fonseca: Microbiology and Immunology, Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa
Robert Nadon: McGill University and Genome Quebec Innovation Centre, McGill University
Nahum Sonenberg: McGill University

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Targeting mTORC1 is a highly promising strategy in cancer therapy. Suppression of mTORC1 activity leads to rapid dephosphorylation of eIF4E-binding proteins (4E-BP1–3) and subsequent inhibition of mRNA translation. However, how the different 4E-BPs affect translation during prolonged use of mTOR inhibitors is not known. Here we show that the expression of 4E-BP3, but not that of 4E-BP1 or 4E-BP2, is transcriptionally induced during prolonged mTORC1 inhibition in vitro and in vivo. Mechanistically, our data reveal that 4E-BP3 expression is controlled by the transcription factor TFE3 through a cis-regulatory element in the EIF4EBP3 gene promoter. CRISPR/Cas9-mediated EIF4EBP3 gene disruption in human cancer cells mitigated the inhibition of translation and proliferation caused by prolonged treatment with mTOR inhibitors. Our findings show that 4E-BP3 is an important effector of mTORC1 and a robust predictive biomarker of therapeutic response to prolonged treatment with mTOR-targeting drugs in cancer.

Date: 2016
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DOI: 10.1038/ncomms11776

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