Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.
Nat Commun. 2017 Dec 20;8(1):2207. doi: 10.1038/s41467-017-02243-3.
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.
4E-BP1 表达的缺失与癌症的进展和对 mTOR 抑制剂的耐药性有关，但肿瘤中 4E-BP1 下调的机制尚不清楚。在这里，我们鉴定出 Snail 是 4E-BP1 的一个强有力的转录抑制因子。我们发现，在癌细胞系和临床标本中，4E-BP1 的表达与 Snail 水平呈负相关。Snail 结合到人类 4E-BP1 启动子中的三个 E 盒上，抑制 4E-BP1 的转录。在缺乏 Snail 的癌细胞系中异位表达 Snail 会显著抑制 4E-BP1 的表达，促进多核糖体中帽依赖性翻译，并降低 mTOR 激酶抑制剂的抗增殖作用。相反，Snail 功能的遗传和药理学抑制通过增强 4E-BP1 对细胞增殖和肿瘤生长的翻译抑制作用来恢复 4E-BP1 的表达，并使癌细胞对 mTOR 激酶抑制剂敏感。我们的研究揭示了肿瘤发生中的一个关键的 Snail-4E-BP1 信号轴，并为靶向 Snail 以改善 mTOR 靶向治疗提供了依据。
