Fraile Julia M, Manchado Eusebio, Lujambio Amaia, Quesada Víctor, Campos-Iglesias Diana, Webb Thomas R, Lowe Scott W, López-Otín Carlos, Freije José M P
From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
the Centro de Investigación Biomédica en Red de Cáncer, Spain.
J Biol Chem. 2017 Mar 10;292(10):4164-4175. doi: 10.1074/jbc.M116.762757. Epub 2017 Feb 1.
is the most frequently mutated oncogene in human cancer, but its therapeutic targeting remains challenging. Here, we report a synthetic lethal screen with a library of deubiquitinases and identify , which encodes an essential splicing factor, as a critical gene for the viability of KRAS-dependent cells. We show that splicing fidelity inhibitors decrease preferentially the proliferation rate of KRAS-active cells. Moreover, depletion of , encoding an USP39-interacting splicing factor, also reduces the viability of these cells. In agreement with these results, USP39 depletion caused a significant reduction in pre-mRNA splicing efficiency, as demonstrated through RNA-seq experiments. Furthermore, we show that is up-regulated in lung and colon carcinomas and its expression correlates with levels and poor clinical outcome. Accordingly, our work provides critical information for the development of splicing-directed antitumor treatments and supports the potential of USP39-targeting strategies as the basis of new anticancer therapies.
是人类癌症中最常发生突变的致癌基因，但其治疗靶向仍然具有挑战性。在此，我们报告了一项使用去泛素酶文库的合成致死筛选，并鉴定出编码一种必需剪接因子的 ，作为KRAS依赖性细胞生存能力的关键基因。我们表明，剪接保真度抑制剂优先降低KRAS活性细胞的增殖率。此外，编码与USP39相互作用的剪接因子的 的缺失也降低了这些细胞的生存能力。与这些结果一致，通过RNA测序实验证明，USP39的缺失导致前体mRNA剪接效率显著降低。此外，我们表明 在肺癌和结肠癌中上调，其表达与 水平及不良临床结果相关。因此，我们的工作为开发剪接导向的抗肿瘤治疗提供了关键信息，并支持以USP39靶向策略为基础的新抗癌疗法的潜力。
