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Abstract

Volume 23, Issue 3 (May 2021) 23, 266–272; 10.4103/aja.aja_63_20

Methylated CpG dinucleotides in the 5-α reductase 2 gene may explain finasteride resistance in benign prostatic enlargement patients

Zhe-Min Lin1, Dong-Dong Fan2, Song Jin3, Zhan-Liang Liu1, Yi-Nong Niu1

1 Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100016, China
2 Department of Urology, Beijing Miyun Teaching Hospital, Capital Medical University, Beijing 101500, China
3 Department of Urology, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China

Correspondence: Dr. YN Niu (18601020160@163.com)

Date of Submission 25-Feb-2020 Date of Acceptance 14-Jul-2020 Date of Web Publication 20-Nov-2020

Abstract

The inhibition of 5-α reductase type 2 (SRD5A2) by finasteride is commonly used for the management of urinary obstruction resulting from benign prostatic enlargement (BPE). Certain BPE patients showing no SRD5A2 protein expression are resistant to finasteride therapy. Our previous work showed that methylated cytosine-phosphate-guanine (CpG) islands in the SRD5A2 gene might account for the absence or reduction of SRD5A2 protein expression. Here, we found that the expression of the SRD5A2 protein was variable and that weak expression of the SRD5A2 protein (scored 0–100) occurred in 10.0% (4/40) of benign adult prostates. We showed that the expression of SRD5A2 was negatively correlated with DNA methyltransferase 1 (DNMT1) expression. In vitro SRD5A2-negative BPH-1 cells were resistant to finasteride treatment, and SRD5A2 was re-expressed in BPH-1 cells when SRD5A2 was demethylated by 5-Aza-2'-deoxycytidine (5-Aza-CdR) or N-phthalyl-L-tryptophan (RG108). Furthermore, we determined the exact methylation ratios of CpG dinucleotides in a CpG island of SRD5A2 through MassArray quantitative methylation analysis. Ten methylated CpG dinucleotides, including four CpG dinucleotides in the promoter and six CpG dinucleotides in the first exon, were found in a CpG island located from −400 bp to +600 bp in SRD5A2, which might lead to the silencing of SRD5A2 and the absence or reduction of SRD5A2 protein expression. Finasteride cannot exert a therapeutic effect on patients lacking SRD5A2, which may partially account for the resistance to finasteride observed in certain BPE patients.

Keywords: 5-α reductase; benign prostatic enlargement; CpG island; methylated CpG dinucleotides; methylation

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