Recurrent SKIL-activating rearrangements in ETS-negative prostate cancer.
Prostate cancer is the third most common cause of male cancer death in developed countries, and one of the most comprehensively characterized human cancers. Roughly 60% of prostate cancers harbor gene fusions that juxtapose ETS-family transcription factors with androgen regulated promoters. A second subtype, characterized by SPINK1 overexpression, accounts for 15% of prostate cancers. Here we report the discovery of a new prostate cancer subtype characterized by rearrangements juxtaposing the SMAD inhibitor SKIL with androgen regulated promoters, leading to increased SKIL expression. SKIL fusions were found in 6 of 540 (1.1%) prostate cancers and 1 of 27 (3.7%) cell lines and xenografts. 6 of 7 SKIL-positive cancers were negative for ETS overexpression, suggesting mutual exclusivity with ETS fusions. SKIL knockdown led to growth arrest in PC-3 and LNCaP cell line models of prostate cancer, and its overexpression led to increased invasiveness in RWPE-1 cells. The role of SKIL as a prostate cancer oncogene lends support to recent studies on the role of TGF-β signaling as a rate-limiting step in prostate cancer progression. Our findings highlight SKIL as an oncogene and potential therapeutic target in 1-2% of prostate cancers, amounting to an estimated 10,000 cancer diagnoses per year worldwide.
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Institute of Biosciences and Medical Technology - BioMediTech, Tampere University of Technology, Tampere, Finland.
Matti
M
Annala
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Institute of Biosciences and Medical Technology - BioMediTech, Tampere University of Technology, Tampere, Finland.
Kati
K
Kivinummi
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Joonas
J
Tuominen
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Serdar
S
Karakurt
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Institute of Biosciences and Medical Technology - BioMediTech, Tampere University of Technology, Tampere, Finland.
Kirsi
K
Granberg
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Leena
L
Latonen
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Institute of Biosciences and Medical Technology - BioMediTech, Tampere University of Technology, Tampere, Finland.
Antti
A
Ylipää
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Liisa
L
Sjöblom
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Institute of Biosciences and Medical Technology - BioMediTech, Tampere University of Technology, Tampere, Finland.
Pekka
P
Ruusuvuori
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Outi
O
Saramäki
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Kirsi M
KM
Kaukoniemi
Institute of Biosciences and Medical Technology - BioMediTech, Tampere University of Technology, Tampere, Finland.
Olli
O
Yli-Harja
Department of Urology, University of Washington, Seattle, WA, USA.
Robert L
RL
Vessella
Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland.
Teuvo L J
TL
Tammela
Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Wei
W
Zhang
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
Tapio
T
Visakorpi
Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Tampere, Finland.|Institute of Biosciences and Medical Technology - BioMediTech, Tampere University of Technology, Tampere, Finland.
Matti
M
Nykter
D000818:Animals; D045744:Cell Line, Tumor; D015331:Cohort Studies; D055785:Gene Knockdown Techniques; D015321:Gene Rearrangement; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000145:classification* / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D014162:Transfection
D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; C060615:SKIL protein, human
SKIL; fusion gene; prostate cancer; sequencing