Article ; Online: Methylated CpG dinucleotides in the 5-α reductase 2 gene may explain finasteride resistance in benign prostatic enlargement patients.
2020 Volume 23, Issue 3, Page(s) 266–272
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 ... ...
| 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. |
|---|---|
| MeSH term(s) | 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/analysis ; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/blood ; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics ; Drug Resistance/drug effects ; Finasteride/antagonists & inhibitors ; Finasteride/therapeutic use ; Humans ; Male ; Membrane Proteins/analysis ; Membrane Proteins/blood ; Membrane Proteins/genetics ; Methylation/drug effects ; Prostatic Hyperplasia/drug therapy ; Prostatic Hyperplasia/physiopathology |
| Chemical Substances | Membrane Proteins ; Finasteride (57GNO57U7G) ; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase (EC 1.3.99.5) ; SRD5A2 protein, human (EC 1.3.99.5) |
| Language | English |
| Publishing date | 2020-11-26 |
| Publishing country | China |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2075824-8 |
| ISSN | 1745-7262 ; 1008-682X |
| ISSN (online) | 1745-7262 |
| ISSN | 1008-682X |
| DOI | 10.4103/aja.aja_63_20 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 5739: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.