Cai Weijia, Ye Qing, She Qing-Bai
Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA. Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY, USA. These authors contributed equally to this work.
Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA. Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY, USA.
Oncotarget. 2014 Aug 15;5(15):6015-27. doi: 10.18632/oncotarget.2109.
The cap-dependent translation is frequently deregulated in a variety of cancers associated with tumor progression. However, the molecular basis of the translation activation for metastatic progression of cancer remains largely elusive. Here, we demonstrate that activation of cap-dependent translation by silencing the translational repressor 4E-BP1 causes cancer epithelial cells to undergo epithelial-mesenchymal transition (EMT), which is associated with selective upregulation of the EMT inducer Snail followed by repression of E-cadherin expression and promotion of cell migratory and invasive capabilities as well as metastasis. Conversely, inhibition of cap-dependent translation by a dominant active mutant 4E-BP1 effectively downregulates Snail expression and suppresses cell migration and invasion. Furthermore, dephosphorylation of 4E-BP1 by mTORC1 inhibition or directly targeting the translation initiation also profoundly attenuates Snail expression and cell motility, whereas knockdown of 4E-BP1 or overexpression of Snail significantly rescues the inhibitory effects. Importantly, 4E-BP1-regulated Snail expression is not associated with its changes in the level of transcription or protein stability. Together, these findings indicate a novel role of 4E-BP1 in the regulation of EMT and cell motility through translational control of Snail expression and activity, and suggest that targeting cap-dependent translation may provide a promising approach for blocking Snail-mediated metastatic potential of cancer.
在与肿瘤进展相关的多种癌症中，帽依赖性翻译常常失调。然而，癌症转移进展过程中翻译激活的分子基础在很大程度上仍不清楚。在此，我们证明通过沉默翻译抑制因子4E-BP1激活帽依赖性翻译会导致癌细胞上皮细胞发生上皮-间质转化（EMT），这与EMT诱导因子Snail的选择性上调相关，随后E-钙黏蛋白表达受到抑制，细胞迁移和侵袭能力以及转移能力增强。相反，用显性活性突变体4E-BP1抑制帽依赖性翻译可有效下调Snail表达并抑制细胞迁移和侵袭。此外，通过抑制mTORC1使4E-BP1去磷酸化或直接靶向翻译起始也会显著减弱Snail表达和细胞运动性，而敲低4E-BP1或过表达Snail可显著挽救这种抑制作用。重要的是，4E-BP1调节的Snail表达与其转录水平或蛋白质稳定性的变化无关。总之，这些发现表明4E-BP1在通过对Snail表达和活性的翻译控制来调节EMT和细胞运动性方面具有新作用，并表明靶向帽依赖性翻译可能为阻断Snail介导的癌症转移潜能提供一种有前景的方法。
