USP39 Deubiquitinase Is Essential for
| Autor: | Julia M, Fraile, Eusebio, Manchado, Amaia, Lujambio, Víctor, Quesada, Diana, Campos-Iglesias, Thomas R, Webb, Scott W, Lowe, Carlos, López-Otín, José M P, Freije |
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| Rok vydání: | 2016 |
| Předmět: |
Lung Neoplasms
Reverse Transcriptase Polymerase Chain Reaction Blotting Western Mice Nude Apoptosis Prognosis Real-Time Polymerase Chain Reaction Xenograft Model Antitumor Assays Proto-Oncogene Proteins p21(ras) Survival Rate Mice Colonic Neoplasms Mutation Tumor Cells Cultured Animals Humans RNA RNA Messenger Ubiquitin-Specific Proteases Cell Proliferation |
| Zdroj: | The Journal of biological chemistry. 292(10) |
| ISSN: | 1083-351X |
| Popis: | 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 RNA-seq 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. |
| Databáze: | OpenAIRE |
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