153090

DAB2IP

AF9Q34|AIP1|DIP1/2;DAB2 interacting protein;DAB2IP;DAB2 interacting protein

ASK-interacting protein 1|ASK1-interacting protein 1|DAB2 interaction protein|DAB2-interacting protein|DOC-2/DAB2 interactive protein|disabled homolog 2-interacting protein|nGAP-like protein

9q33.1-q33.3

protein-coding

Count: 2; Generif,UniProt

BACKGROUND: The consistent finding of a genetic susceptibility to prostate cancer suggests that there are germline sequence variants predisposing individuals to this disease. These variants could be useful in screening and treatment. METHODS: We performed an exploratory genome-wide association scan in 498 men with aggressive prostate cancer and 494 control subjects selected from a population-based case-control study in Sweden. We combined the results of this scan with those for aggressive prostate cancer from the publicly available cancer Genetic Markers of Susceptibility (CGEMS) Study. Single-nucleotide polymorphisms (SNPs) that showed statistically significant associations with the risk of aggressive prostate cancer based on two-sided allele tests were tested for their association with aggressive prostate cancer in two independent study populations composed of individuals of European or African American descent using one-sided tests and the genetic model (dominant or additive) associated with the lowest value in the exploratory study. RESULTS: Among the approximately 60,000 SNPs that were common to our study and CGEMS, we identified seven that had a similar (positive or negative) and statistically significant (P<.01) association with the risk of aggressive prostate cancer in both studies. Analysis of the distribution of these SNPs among 1032 prostate cancer patients and 571 control subjects of European descent indicated that one, rs1571801, located in the DAB2IP gene, which encodes a novel Ras GTPase-activating protein and putative prostate tumor suppressor, was associated with aggressive prostate cancer (one-sided P value = .004). The association was also statistically significant in an African American study population that included 210 prostate cancer patients and 346 control subjects (one-sided P value = .02). CONCLUSION: A genetic variant in DAB2IP may be associated with the risk of aggressive prostate cancer and should be evaluated further.

hDAB2IP (human DAB2 (also known as DOC-2) interactive protein) is a novel GTPase-activating protein for modulating the Ras-mediated signal pathway. We demonstrate that the down-regulation of hDAB2IP mRNA in prostate cancer (PCa) cells is regulated by transcriptional levels. Analysis of the hDAB2IP promoter revealed that it is a typical TATA-less promoter containing many GC-rich sequences. In this study, we delineated the potential impact of the epigenetic control of the hDAB2IP promoter on its gene regulation in PCa. Acetylhistone H3 was associated with the hDAB2IP promoter, and CpG islands remained almost unmethylated in normal prostatic epithelia, but not in PCa cell lines. Our data further indicated that trichostatin A (histone deacetylase inhibitor) and 5'-aza-2'-deoxycytidine (DNA hypomethylation agent) acted cooperatively in modulating hDAB2IP gene expression in PCa, whereas histone acetylation played a more significant role in this event. Moreover, a core promoter sequence from the hDAB2IP gene responsible for these treatments was identified. We therefore conclude that epigenetic regulation plays a potential role in regulating hDAB2IP expression in PCa and that these results also provide a new therapeutic strategy for PCa patients.