Department of Oncological Sciences, Huntsman Cancer Institute, School of Medicine, University of Utah.
Mol Cell Biol. 2013 Nov;33(22):4448-60. doi: 10.1128/MCB.00241-13. Epub 2013 Sep 16.
Oncogenic transformation in Ewing sarcoma is caused by EWS/FLI, an aberrant transcription factor fusion oncogene. Glioma-associated oncogene homolog 1 (GLI1) is a critical target gene activated by EWS/FLI, but the mechanism by which GLI1 contributes to the transformed phenotype of Ewing sarcoma was unknown. In this work, we identify keratin 17 (KRT17) as a direct downstream target gene upregulated by GLI1. We demonstrate that KRT17 regulates cellular adhesion by activating AKT/PKB (protein kinase B) signaling. In addition, KRT17 is necessary for oncogenic transformation in Ewing sarcoma and accounts for much of the GLI1-mediated transformation function but via a mechanism independent of AKT signaling. Taken together, our data reveal previously unknown molecular functions for a cytoplasmic intermediate filament protein, KRT17, in coordinating EWS/FLI- and GLI1-mediated oncogenic transformation and cellular adhesion in Ewing sarcoma.
尤文肉瘤中的致癌转化是由 EWS/FLI 引起的，这是一种异常的转录因子融合致癌基因。神经胶质瘤相关癌基因同源物 1 (GLI1) 是 EWS/FLI 激活的关键靶基因，但 GLI1 促进尤文肉瘤转化表型的机制尚不清楚。在这项工作中，我们确定角蛋白 17 (KRT17) 是由 GLI1 上调的直接下游靶基因。我们证明 KRT17 通过激活 AKT/PKB (蛋白激酶 B) 信号来调节细胞黏附。此外，KRT17 对于尤文肉瘤的致癌转化是必需的，并且在很大程度上解释了 GLI1 介导的转化功能，但通过一种独立于 AKT 信号的机制。总之，我们的数据揭示了细胞质中间丝蛋白 KRT17 在协调 EWS/FLI 和 GLI1 介导的致癌转化和尤文肉瘤细胞黏附中的以前未知的分子功能。
