USP39 Deubiquitinase Is Essential for KRAS Oncogene-driven Cancer.
J Biol Chem
; 292(10): 4164-4175, 2017 03 10.
Article
in En
| MEDLINE
| ID: mdl-28154181
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proto-Oncogene Proteins p21(ras)
/
Colonic Neoplasms
/
Ubiquitin-Specific Proteases
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Lung Neoplasms
/
Mutation
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Biol Chem
Year:
2017
Type:
Article
Affiliation country:
Spain