Snail Determines the Therapeutic Response to MTOR Kinase Inhibitors by Transcriptional Repression of 4E-BP1

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Dec 22

PMID 29263324

Citations 20

Authors

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

Affiliations

Soon will be listed here.

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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