Araya Selene, Kratschmar Denise V, Tsachaki Maria, Stücheli Simon, Beck Katharina R, Odermatt Alex
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
J Steroid Biochem Mol Biol. 2017 Jul;171:288-295. doi: 10.1016/j.jsbmb.2017.04.013. Epub 2017 Apr 27.
DHRS7 (SDR34C1) has been associated with potential tumor suppressor effects in prostate cancer; however, its function remains largely unknown. Recent experiments using purified recombinant human DHRS7 suggested several potential substrates, including the steroids cortisone and Δ4-androstene-3,17-dione (androstenedione). However, the substrate and cofactor concentrations used in these experiments were very high and the physiological relevance of these observations needed to be further investigated. In the present study, recombinant human DHRS7 was expressed in intact HEK-293 cells in order to investigate whether glucocorticoids and androgens serve as substrates at sub-micromolar concentrations and at physiological cofactor concentrations. Furthermore, the membrane topology of DHRS7 was revisited using redox-sensitive green-fluorescent protein fusions in living cells. The results revealed that (1) cortisone is a substrate of DHRS7; however, it is not reduced to cortisol but to 20β-dihydrocortisone, (2) androstenedione is not a relevant substrate of DHRS7, (3) DHRS7 catalyzes the oxoreduction of 5α-dihydrotestosterone (5αDHT) to 3α-androstanediol (3αAdiol), with a suppressive effect on androgen receptor (AR) transcriptional activity, and (4) DHRS7 is anchored in the endoplasmic reticulum membrane with a cytoplasmic orientation. Together, the results show that DHRS7 is a cytoplasmic oriented enzyme exhibiting 3α/20β-hydroxysteroid dehydrogenase activity, with a possible role in the modulation of AR function. Further research needs to address the physiological relevance of DHRS7 in the inactivation of 5αDHT and AR regulation.
DHRS7（SDR34C1）与前列腺癌中的潜在肿瘤抑制作用相关；然而，其功能在很大程度上仍不清楚。最近使用纯化的重组人DHRS7进行的实验表明了几种潜在的底物，包括类固醇可的松和Δ4-雄烯-3,17-二酮（雄烯二酮）。然而，这些实验中使用的底物和辅因子浓度非常高，这些观察结果的生理相关性需要进一步研究。在本研究中，重组人DHRS7在完整的HEK-293细胞中表达，以研究糖皮质激素和雄激素在亚微摩尔浓度和生理辅因子浓度下是否作为底物。此外，利用活细胞中对氧化还原敏感的绿色荧光蛋白融合体重新研究了DHRS7的膜拓扑结构。结果表明：（1）可的松是DHRS7的底物；然而，它不是还原为皮质醇，而是还原为20β-二氢可的松；（2）雄烯二酮不是DHRS7的相关底物；（3）DHRS7催化5α-二氢睾酮（5αDHT）氧化还原为3α-雄烷二醇（3αAdiol），对雄激素受体（AR）转录活性有抑制作用；（4）DHRS7以细胞质方向锚定在内质网膜上。总之，结果表明DHRS7是一种具有细胞质方向的酶，表现出3α/20β-羟基类固醇脱氢酶活性，可能在调节AR功能中发挥作用。进一步的研究需要解决DHRS7在5αDHT失活和AR调节中的生理相关性。
