USP39 Deubiquitinase Is Essential forKRASOncogene-driven Cancer.
KRASis 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 identifyUSP39, 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 ofDHX38, 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 thatUSP39is up-regulated in lung and colon carcinomas and its expression correlates withKRASlevels 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.
From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.|the Centro de Investigación Biomédica en Red de Cáncer, Spain.
Julia M
JM
Fraile
the Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, and.
Eusebio
E
Manchado
the Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, and.
Amaia
A
Lujambio
From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.|the Centro de Investigación Biomédica en Red de Cáncer, Spain.
Víctor
V
Quesada
From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
Diana
D
Campos-Iglesias
the Division of Biosciences, SRI International, Menlo Park, California 94025.
Thomas R
TR
Webb
the Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, and.
Scott W
SW
Lowe
From the Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.|the Centro de Investigación Biomédica en Red de Cáncer, Spain.
Carlos
C
López-Otín
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.|the Centro de Investigación Biomédica en Red de Cáncer, Spain.
José M P
JM
Freije
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C117307:KRAS protein, human; D012333:RNA, Messenger; C579218:USP39 protein, human; D064570:Ubiquitin-Specific Proteases; D016283:Proto-Oncogene Proteins p21(ras)
RNA splicing; degradome; deubiquitylation (deubiquitination); non-oncogene addiction; protease; short hairpin RNA (shRNA); spliceosome; synthetic lethality