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

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.

Epigenetics. 2020 Jul 13 [Epub ahead of print]

Farideh Shafiee-Kermani, Skyla T Carney, Dereje Jima, Utibe C Utin, LaNeisha B Farrar, Melvin O Oputa, Marcono R Hines, H Karimi Kinyamu, Kevin W Trotter, Trevor K Archer, Cathrine Hoyo, Beverly H Koller, Stephen J Freedland, Delores J Grant

Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University , 1801 Fayetteville Street, Durham, NC 27707., Bioinformatics Research Center, Center of Human Health and the Environment, North Carolina State University , Ricks Hall, 1 Lampe Dr 27607, Raleigh, NC 27606., Chromatin and Gene Expression Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park , North Carolina, 27709., Epidemiology and Environmental Epigenomics Laboratory, Department of Biological Sciences, Center of Human Health and the Environment, North Carolina State University 3229 Broughton Hall, Raleigh, NC 27606., Department of Genetics UNC School of Medicine, University of North Carolina at Chapel Hill , 5073 Genetic Medicine Bldg, NC 27599., Cedars-Sinai Health System Center for Integrated Research on Cancer and Lifestyles , Cancer Genetics and Prevention Program, Surgery, 8700 Beverly Blvd, Los Angeles, CA 90048., Department of Biological and Biomedical Sciences, Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, Center of Human Health and the Environment, North Carolina State University , Raleigh, NC 27606.