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

  • Nat Commun. 2017 Dec 20;8(1):2207. doi: 10.1038/s41467-017-02243-3.
Jun Wang  1  2 ,  Qing Ye  1  2 ,  Yanan Cao  1  2 ,  Yubin Guo  1  3 ,  Xiuping Huang  1  3 ,  Wenting Mi  1  3 ,  Side Liu  3 ,  Chi Wang  1  4 ,  Hsin-Sheng Yang  1  5 ,  Binhua P Zhou  1  6 ,  B Mark Evers  1  7 ,  Qing-Bai She  8  9
Affiliations
  • 1. Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
  • 2. Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
  • 3. Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
  • 4. Department of Biostatistics, University of Kentucky College of Public Health, Lexington, KY, 40506, USA.
  • 5. Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
  • 6. Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
  • 7. Department of Surgery, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
  • 8. Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40506, USA. [email protected].
  • 9. Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40506, USA. [email protected].
PMID: 29263324 DOI: 10.1038/s41467-017-02243-3
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.

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