USP39 Deubiquitinase Is Essential for KRAS Oncogene-driven Cancer
USP39 Deubiquitinase Is Essential for KRAS Oncogene-driven Cancer
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DOI：
10.1074/jbc.m116.762757
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发表时间：
2017-03-10
影响因子：
4.8
通讯作者：
Freije, Jose M. P.
中科院分区：
文献类型：
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作者：
Fraile, Julia M.;Manchado, Eusebio;Freije, Jose M. P.
KRAS是人类癌症中最常见的突变癌基因，但其治疗靶向仍然具有挑战性。在这里，我们报告了一个合成的致死屏幕与库的去泛素化酶和识别USP39，它编码一个重要的剪接因子，作为一个关键基因的KRAS依赖性细胞的活力。我们发现，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USP39相互作用剪接因子的DHX38的耗尽也降低了这些细胞的活力。与这些结果一致，USP39缺失导致前体mRNA剪接效率显著降低，如通过RNAseq实验所证明的。此外，我们发现USP39在肺癌和结肠癌中上调，其表达与KRAS水平和不良临床结局相关。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USP39靶向策略作为新抗癌疗法基础的潜力。
KRAS 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 USP39, 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 DHX38, 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 RNAseq experiments. Furthermore, we show that USP39 is up-regulated in lung and colon carcinomas and its expression correlates with KRAS 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.