USP39 deubiquitinase is essential for KRAS oncogene-driven cancer

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

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish
Pages (from-to)4164-4175
Number of pages12
JournalJournal of Biological Chemistry
Issue number10
StatePublished - 10 Mar 2017


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