Chd1 And Spop Synergistically Protect Prostate Epithelial Cells From Dna Damage

Background Recent genomic profiling has identified a subtype of prostate cancer (PCa) characterized by two key genetic alterations: missense mutation of speckle-type POZ protein (SPOP) and homozygous deletion of chromodomain helicase DNA-binding protein 1 (CHD1). Mutually exclusive with E26 transformation-specific (ETS) rearrangements, this subtype displays high genomic instability. Previous studies indicate that deficientSPOPorCHD1alone leads to feeble prostate abnormalities and each protein is involved in DNA damage response (DDR). It remains to be determined whether CHD1 and SPOP cooperate to suppress prostate tumorigenesis and DDR. Methods Prostate-specific single or double knockout ofSpopandChd1was generated with the Cre/loxP system in mice. Wild-type or mutantSPOP(F102C, F133V) overexpression andCHD1knockdown with short hairpin RNA were created in human benign prostatic hyperplasia cell line BPH1. The levels of DNA damage and homologous recombination repair were measured by immunofluorescence staining of gamma H2AX and RAD51, respectively. Results Spop/Chd1double-knockout mice displayed prostatic intraepithelial neoplasia at both young (3 months) and old (12 months) ages and failed to generate prostate adenocarcinoma. Compared with wild-type or single-knockout mice, the double-knockout prostate harbored moderately higher proliferating cells and dramatically augmented the level of gamma H2AX staining, although androgen receptor-positive cells and apoptotic cells remained at a similar level. In BPH1 cell line,SPOPmutant overexpression andCHD1silencing synergistically sensitized the cells to DNA damage by camptothecin, an inducer of double-strand breaks. Conclusions Our results indicate that SPOP and CHD1 can synergistically promote repair of naturally occurring or chemically induced DNA damages in prostate epithelial cells. Regarding the progression of the SPOP/CHD1 subtype of PCa, other functionally complementary drivers warrant further identification. The clinical implication is that this subtype of PCa may be particularly sensitive to poly(ADP-ribose) polymerase inhibitors or DNA-damaging agents.