Expression of UDP Glucuronosyltransferases 2B15 and 2B17 Is Associated with Methylation Status in Prostate Cancer cells

Abstract

Studies have suggested that abrogated expression of detoxification enzymes, UGT2B15 and UGT2B17, are associated with prostate tumor risk and progression. We investigated the role of EGF on the expression of these enzymes since it interacts with signaling pathways to also affect prostate tumor progression and is additionally associated with decreased DNA methylation. The expression of UGT2B15, UGT2B17, de novo methyltransferases, DNMT3A and DNMT3B was assessed in prostate cancer cells (LNCaP) treated with EGF; an EGFR inhibitor PD16893 and the methyltransferase inhibitor, 5-azacytidine, respectively. The results showed that EGF treatment decreased levels of expression for all four genes and that expression was reversed by PD16893. Treatment with 5- azacytidine, markedly decreased expression of UGT2B15 and UGT2B17 over 85% as well as significantly decreased expression of DNMT3B, but not the expression of DNMT3A. DNMT3B siRNA treated LNCaP cells had decreased expression for UGT2B15 and UGT2B17, while DNMT3A siRNA treated cells only moderately decreased UGT2B15 expression. Treatment with DNMT methyltransferase inhibitor, RG108 significantly decreased UGT2B17 expression. Additionally, methylation differences between prostate cancer samples and benign prostate samples from an Illumina 450K Methylation Array study were assessed. The results taken together suggest that hypomethylation of the UGT2B15 and UGT2B17 genes contributes to increased risk of prostate cancer and may provide a putative biomarker or epigenetic target for chemotherapeutics. Mechanistic studies are warranted to determine the role of the methylation marks in prostate cancer.