PSA/KLK3 AREI promoter polymorphism alters androgen receptor binding and is associated with prostate cancer susceptibility

Abstract

The proximal promoter of the kallikrein-related peptidase 3 gene (KLK3/PSA) contains a single-nucleotide polymorphism (G-158A) located within the second canonical half-site for the prostate-specific antigen (PSA) androgen response element 1 (AREI). Previous studies suggest that this polymorphism may be associated with higher PSA levels and increase prostate cancer risk. We have investigated the potential functional significance of this polymorphism and its association with prostate cancer susceptibility by genotyping the G-158A polymorphism in 209 men diagnosed with prostate cancer and 223 healthy control men in an Australian Caucasian population. Functional analyses of PSA AREI demonstrated that the A allele increased binding of AREI to the androgen receptor, as well as increasing transcriptional response to androgens. Association studies of the G-158A polymorphism demonstrated that men with an A/A genotype had a 3-fold increased risk for developing prostate cancer [95% confidence intervals (CIs) = 1.36-6.52] and men with an A/G genotype had a 2.4-fold increased risk (95% CIs = 1.23-4.81). Under a dominant model, the A allele conferred a 2.6-fold increased risk for prostate cancer (95% CIs = 1.37-4.96, P = 0.004). Taken together with the finding that the G-158A polymorphism is associated with an increased risk of prostate cancer in Australian men, our functional data suggest that the presence of the A allele in AREI may, in part, account for the altered PSA regulation seen in prostate cancer.

Kallikrein-Related Peptidase 3(KLK3/PSA) Single Nucleotide Polymorphisms and Ovarian Cancer Survival

“…Moreover, there are several other KLKs that are upregulated in ovarian cancer versus normal tissue, but which are markers of improved prognosis, namely KLK8, KLK9 and KLK14 (Borgono et al, 2004;Obiezu & Diamandis, 2005). Although it is perhaps surprising that rs266882 was not found to be associated with ovarian cancer survival despite the reported functional significance of this SNP, this may also reflect some fundamental differences in regulation of PSA expression between prostate and ovarian cancer, namely differential tissue-specific co-regulator binding at the allelic change in the AREI as suggested for rs266882 in prostate cell lines (Lai et al, 2007), which may drive differential ovarian expression.…”

Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases

“…Numerous subsequent studies have revealed conflicting results. Some have reported an association with the same allele as the original study (Gsur et al , 2002 ;Medeiros et al , 2002 ;Cicek et al , 2005 ;Lai et al , 2007 ), while others have reported either a significant association in the opposite direction (Chiang et al , 2004 ;Binnie et al , 2005 ) or no association for this SNP (Wang et al , 2003 ;Salinas et al , 2005 ;Mononen et al , 2006 ;Severi et al , 2006 ;Cunningham et al , 2007 ;Pal et al , 2007 ;Penney et al , 2011 ). A meta-analysis of all studies published up until 2008 reported no evidence of association with prostate cancer risk overall (Supplementary Table 1; Jesser et al , 2008 ).…”

“…Functional studies on rs266882 attribute KLK3 gene expression alteration to differential binding of ARE1 to the androgen receptor (Table 1) and enhanced transcriptional response to androgens. They also show increased prostate cancer susceptibility in the presence of A/A genotype (three-fold risk) and A/G genotype (2.4-fold risk; Lai et al , 2007 ).…”

Genetic variants in the distal enhancer region of the PSA gene and their implication in the occurrence of advanced prostate cancer

“…Several single nucleotide polymorphisms in this gene and their possible association with the risk of prostate cancer and serum PSA levels have been studied. Until recently, the single nucleotide polymorphism (SNP) at -158 G/A has been the most studied polymorphism of the PSA gene, but no consensus about its significance in prostate cancer has been reached thus far (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Cramer et al reported a possible association between SNPs in the enhancer region of the PSA gene and serum PSA levels (22).…”