Vitamin D receptor-binding site variants affect prostate cancer progression

Vitamin D is an important modulator of cellular proliferation through the vitamin D receptor (VDR) that binds to DNA in the regulatory sequences of target genes. We hypothesized that single nucleotide polymorphisms (SNPs) in VDR-binding sites might affect target gene expression and influence the progression of prostate cancer. Using a genome-wide prediction database, 62 SNPs in VDR-binding sites were selected for genotyping in 515 prostate cancer patients and the findings were replicated in an independent cohort of 411 patients. Prognostic significance on prostate cancer progression was assessed by Kaplan-Meier analysis and the Cox regression model. According to multivariate analyses adjusted for known predictors, HFE rs9393682 was found to be associated with disease progression for localized prostate cancer, and TUSC3 rs1378033 was associated with progression for advanced prostate cancer in both cohorts. Vitamin D treatment inhibited HFE mRNA expression, and down-regulation of HFE by transfecting small interfering RNA suppressed PC-3 human prostate cancer cell proliferation and wound healing ability. In contrast, vitamin D treatment induced TUSC3 expression, and silencing TUSC3 promoted prostate cancer cell growth and migration. Further analysis of an independent microarray dataset confirmed that low TUSC3 expression correlated with poor patient prognosis. Our results warrant further studies using larger cohorts. This study identifies common variants in VDR-binding sites as prognostic markers of prostate cancer progression and HFE and TUSC3 as plausible susceptibility genes.