期刊
ONCOTARGET
卷 6, 期 8, 页码 6235-6250出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3359
关键词
prostate cancer; sequencing; fusion gene; SKIL
资金
- Finnish Funding Agency for Technology and Innovation Finland Distinguished Professor programme
- Academy of Finland [269474, 251790, 127187]
- Sigrid Juselius Foundation
- Emil Aaltonen Foundation
- Cancer Society of Finland
- Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital [9P053, 9N087]
- EU-FP7 Marie Curie Integrated Training Network, PRO-NEST
- National Institutes of Health [U24CA143835]
- Cancer Genome Atlas project [phs000178.v8.p7]
- Cancer Foundation Finland sr [130133] Funding Source: researchfish
- Academy of Finland (AKA) [251790, 127187, 251790, 127187] Funding Source: Academy of Finland (AKA)
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-beta 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.
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