Recurrent SKIL-activating rearrangements in ETS-negative prostate cancer

• Published in: Oncotarget 2015-03, Vol.6 (8), p.6235-6250
• Main Authors: Annala, Matti, Kivinummi, Kati, Tuominen, Joonas, Karakurt, Serdar, Granberg, Kirsi, Latonen, Leena, Ylipää, Antti, Sjöblom, Liisa, Ruusuvuori, Pekka, Saramäki, Outi, Kaukoniemi, Kirsi M, Yli-Harja, Olli, Vessella, Robert L, Tammela, Teuvo L J, Zhang, Wei, Visakorpi, Tapio, Nykter, Matti
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cohort Studies; Gene Knockdown Techniques; Gene Rearrangement; Heterografts; Humans; Intracellular Signaling Peptides and Proteins - biosynthesis; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; Mice; Middle Aged; Prostatic Neoplasms - classification; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-ets - genetics; Proto-Oncogene Proteins c-ets - metabolism; Research Paper; Transcriptome; Transfection
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3359

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.