Recurrent SKIL-activating rearrangements in ETS-negative prostate cancer

Oncotarget
Matti AnnalaMatti Nykter

Abstract

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, amo...Continue Reading

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Citations

Mar 5, 2016·PloS One·Liisa SjöblomTapio Visakorpi
Apr 14, 2016·Genes, Chromosomes & Cancer·Leena LatonenTapio Visakorpi
Dec 20, 2015·Genome Medicine·Chandan Kumar-SinhaArul M Chinnaiyan
Dec 23, 2017·Scientific Reports·Kati KivinummiTapio Visakorpi
Apr 27, 2016·Genes, Chromosomes & Cancer·Riikka NurminenJohanna Schleutker
Oct 14, 2020·Nature Reviews. Urology·Filippo PederzoliAndrea Necchi
Feb 27, 2021·Frontiers in Cell and Developmental Biology·Mauro ScaravilliLeena Latonen
Mar 20, 2018·Brain, Behavior, and Immunity·Annesa FlentjeBradley E Aouizerat
May 2, 2021·Cancer Medicine·Sini K EerolaTapio Visakorpi

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Datasets Mentioned

BETA
EGAS00001000526

Methods Mentioned

BETA
xenografts
PCA0056
exome sequencing
Fluorescence
electrophoresis
PCR
Protein Assay
transfection
RNA-seq
DNA-seq

Software Mentioned

ImageJ
Tophat
samtools
ChimeraScan
Illumina pipeline
DesignStudio
Image
samtools rmdup
Bowtie
Breakfast

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