TY - JOUR
T1 - USP39 deubiquitinase is essential for KRAS oncogene-driven cancer
AU - Fraile, Julia M.
AU - Manchado, Eusebio
AU - Lujambio, Amaia
AU - Quesada, Víctor
AU - Campos-Iglesias, Diana
AU - Webb, Thomas R.
AU - Lowe, Scott W.
AU - López-Otín, Carlos
AU - Freije, José M.P.
N1 - Funding Information:
This work was supported by grants from the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (CIBERONC, Plan Feder), Fundación EDP, and Principado de Asturias, Spain. The discovery and synthesis of sudemycin D1 and D6 were supported in part by National Institutes of Health Grant CA140474, the American Lebanese Syrian Associated Charities (ALSAC), and St. Jude Children's Research Hospital. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Drs. J. Valcárcel, M. Balbín, A. Fueyo, D. Rodríguez, and R. Valdés-Mas for helpful comments and assistance, Dr. B. Vogelstein for providing HCT116 and DLD-1 isogenic cell lines, and Dr. J.M. Silva for providing the VSVG-based package system. The Instituto Universitario de Oncología is supported by Fundación Bancaria Caja de Ahorros de Asturias.
Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/3/10
Y1 - 2017/3/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85015071951&partnerID=8YFLogxK
U2 - 10.1074/jbc.M116.762757
DO - 10.1074/jbc.M116.762757
M3 - Article
C2 - 28154181
AN - SCOPUS:85015071951
SN - 0021-9258
VL - 292
SP - 4164
EP - 4175
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
ER -