SPOP mutation leads to genomic instability in prostate cancer

• Published in: eLife Vol. 4
• Main Authors: Boysen, Gunther, Barbieri, Christopher E, Prandi, Davide, Blattner, Mirjam, Chae, Sung-Suk, Dahija, Arun, Nataraj, Srilakshmi, Huang, Dennis, Marotz, Clarisse, Xu, Limei, Huang, Julie, Lecca, Paola, Chhangawala, Sagar, Liu, Deli, Zhou, Pengbo, Sboner, Andrea, de Bono, Johann S, Demichelis, Francesca, Houvras, Yariv, Rubin, Mark A
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications, Ltd 16.09.2015; eLife Sciences Publications Ltd
• Subjects: Animals; cancer genomic; Cell Biology; Cells, Cultured; DNA Breaks, Double-Stranded; DNA Damage - drug effects; DNA Repair; Genomic Instability; Human Biology and Medicine; Humans; Male; Mice; Mice, Transgenic; Mutagens - metabolism; Nuclear Proteins - deficiency; prostate cancer; Prostatic Neoplasms - pathology; Repressor Proteins - deficiency; SPOP; Ubiquitin-Protein Ligase Complexes; Zebrafish; human biology; mouse; prostate cancer; cell biology; SPOP; cancer genomics; medicine; zebrafish; DNA repair; human
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.09207

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. Prostate cancer is the most common type of cancer in men in the UK and USA. Cancers develop when cells in the body acquire genetic mutations that allow the cells to grow rapidly and form a mass known as a tumor. Prostate cancer cells from different individuals can carry different genetic mutations, which affects whether the disease progresses and how the tumors respond to medical treatments. This genetic variety arises in cancer cells partly from a phenomenon known as genomic instability, in which DNA mutations accumulate due to defects in DNA repair. Genetic studies of biopsies taken from human prostate cancers have shown that genomic instability causes chromosomes—the structures in which the cell's DNA is organized—to break and then be stuck back together haphazardly. As a result, fragments of chromosomes can end up in the wrong position, be duplicated, or be lost altogether. All of these mutations could spur on the growth of the tumor. However, it is currently not clear why some prostate cancers are more genomically unstable than others, or what exactly causes this instability. Boysen, Barbieri et al. studied prostate cancer cells taken from patients before they started medical treatment. The experiments show that the cancer cells with high levels of genomic instability also often had mutations in a gene that encodes a protein called SPOP. These mutations occur in about 10 percent of men with prostate cancer and appear early in the development of the tumors. Next, they studied the SPOP protein in zebrafish (which is nearly identical to human SPOP), as well as in mouse and human cells. The experiments show that SPOP normally helps the cell to accurately repair DNA that has been damaged. Mutations in SPOP change the DNA repair process, which lead to genomic instability by increasing the likelihood that broken chromosomes will be stuck back together incorrectly. Further experiments tested drugs known as PARP inhibitors on mouse and human prostate cancer cells. The drugs, which have been recently tested successfully in patients with prostate cancer, block a different method of DNA repair that operates separately to the one that involves SPOP. When both of these pathways were inactivated—one by the SPOP mutation, the other by the drug—the cancer cells died more quickly. Therefore, men that are diagnosed with types of prostate cancer in which the gene that encodes SPOP is mutated might benefit from treatment with PARP inhibitors or other therapies that affect DNA repair.