Role of squalene synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer

Background: We previously conducted a genome-wide linkage analysis of Japanese nuclear families affected with prostate cancer and showed that the susceptibility to prostate cancer was closely linked to D8S550 at 8p23. The role of farnesyl diphosphate farnesyltransferase ( FDFT1 ), which is located under the peak marker D8S550 at 8p23, and squalene synthase, the enzyme encoded by FDFT1 , in prostate cancer was studied. Methods: The association among common variants of FDFT1 with prostate cancer risk, the promoter activities of FDFT1 with different genotypes and the effects of inhibition of squalene synthase were studied, and the FDFT1 transcript levels of human prostate samples were quantified. Results: The A allele of rs2645429 was significantly associated with prostate cancer risk in a Japanese familial prostate cancer population. Rs2645429 was located in the promoter region of FDFT1 , and the AA genotype showed significantly increased promoter activity. The knockdown of FDFT1 mRNA expression or squalene synthase inhibition led to a significant decrease in prostate cancer cell proliferation. Additionally, human prostate cancer specimens expressed significantly higher levels of FDFT1 mRNA compared with noncancerous specimens. Finally, aggressive cancers showed higher transcript levels. Conclusions: FDFT1 and its encoded enzyme, squalene synthase, may play an important role in prostate cancer development and its aggressive phenotypes.