Snail determines the therapeutic response to mTOR kinase inhibitors by transcriptional repression of 4E-BP1

Jun Wang, Qing Ye, Yanan Cao, Yubin Guo, Xiuping Huang, Wenting Mi, Side Liu, Chi Wang, Hsin Sheng Yang, Binhua P. Zhou, B. Mark Evers, Qing Bai She

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Loss of 4E-BP1 expression has been linked to cancer progression and resistance to mTOR inhibitors, but the mechanism underlying 4E-BP1 downregulation in tumors remains unclear. Here we identify Snail as a strong transcriptional repressor of 4E-BP1. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Snail binds to three E-boxes present in the human 4E-BP1 promoter to repress transcription of 4E-BP1. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly represses 4E-BP1 expression, promotes cap-dependent translation in polysomes, and reduces the anti-proliferative effect of mTOR kinase inhibitors. Conversely, genetic and pharmacological inhibition of Snail function restores 4E-BP1 expression and sensitizes cancer cells to mTOR kinase inhibitors by enhancing 4E-BP1-mediated translation-repressive effect on cell proliferation and tumor growth. Our study reveals a critical Snail-4E-BP1 signaling axis in tumorigenesis, and provides a rationale for targeting Snail to improve mTOR-targeted therapies.

Original languageEnglish
Article number2207
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Bibliographical note

Publisher Copyright:
© 2017 The Author(s).

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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