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J Biol Chem. 2017 Mar 10;292(10):4164-4175. doi: 10.1074/jbc.M116.762757. Epub 2017 Feb 1.

USP39 Deubiquitinase Is Essential for KRAS Oncogene-driven Cancer.

Author information

1
From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
2
the Centro de Investigación Biomédica en Red de Cáncer, Spain.
3
the Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, and.
4
the Division of Biosciences, SRI International, Menlo Park, California 94025.
5
From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain, jmpf@uniovi.es.

Abstract

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.

KEYWORDS:

RNA splicing; degradome; deubiquitylation (deubiquitination); non-oncogene addiction; protease; short hairpin RNA (shRNA); spliceosome; synthetic lethality

PMID:
28154181
PMCID:
PMC5354494
DOI:
10.1074/jbc.M116.762757
[Indexed for MEDLINE]
Free PMC Article

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