SPOP mutation leads to genomic instability in prostate cancer.

TitleSPOP mutation leads to genomic instability in prostate cancer.
Publication TypeJournal Article
Year of Publication2015
AuthorsBoysen G, Barbieri CE, Prandi D, Blattner M, Chae S-S, Dahija A, Nataraj S, Huang D, Marotz C, Xu L, Huang J, Lecca P, Chhangawala S, Liu D, Zhou P, Sboner A, de Bono JS, Demichelis F, Houvras Y, Rubin MA
JournalElife
Volume4
Date Published2015 Sep 16
ISSN2050-084X
KeywordsAnimals, Cells, Cultured, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, Genomic Instability, Humans, Male, Mice, Mice, Transgenic, Mutagens, Nuclear Proteins, Prostatic Neoplasms, Repressor Proteins, Ubiquitin-Protein Ligase Complexes, Zebrafish
Abstract

Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA-damaging therapeutics.

DOI10.7554/eLife.09207
Alternate JournalElife
PubMed ID26374986
PubMed Central IDPMC4621745
Grant List2R01CA125612-05A1 / CA / NCI NIH HHS / United States
R01 CA125612 / CA / NCI NIH HHS / United States
K08 CA187417 / CA / NCI NIH HHS / United States
K08CA187417-01 / CA / NCI NIH HHS / United States
PG13-036 / / Prostate Cancer UK / United Kingdom
Related Faculty: 
Andrea Sboner, Ph.D. Pengbo Zhou, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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