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


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.

SUBMITTER: Wang J 

PROVIDER: S-EPMC5738350 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Wang Jun J   Ye Qing Q   Cao Yanan Y   Guo Yubin Y   Huang Xiuping X   Mi Wenting W   Liu Side S   Wang Chi C   Yang Hsin-Sheng HS   Zhou Binhua P BP   Evers B Mark BM   She Qing-Bai QB  

Nature communications 20171220 1


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 canc  ...[more]

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