Transcriptional inhibition of CYP24 by genistein.
1,25 Dihydroxyvitamin D3 (1,25-D3) can be considered an antitumorigenic agent, which can be used in the therapy of malignant diseases such as prostate cancer. In this respect, it is important to note that some prostatic cancer cells express high levels of CYP24, a cytochrome enzyme involved in degradation of 1,25-D3. Genistein, a widely occurring isoflavonoid, inhibits cytochrome enzymes and also exerts antitumorigenic effects. Here, we therefore investigated the effect of genistein on cytochrome enzymes involved in vitamin D metabolism. Treatment of DU-145 prostatic cancer cells with genistein led to a time- and dose-dependent inhibition of CYP24. Additionally CYP27B1 was also inhibited. CYP27B1 is the cytochrome enzyme that synthesizes 1,25-D3. RT-PCR showed that the effect of genistein was mainly due to inhibition of transcription. This often involves the activity of histone deacetylases (HDAC). Thus we tested if the HDAC inhibitor trichostatin A (TSA) reversed the effect of genistein on vitamin D hydroxylases. TSA per se reduced expression of CYP24 mRNA and synergized with genistein to abolish expression after an incubation of 24 h. Importantly, TSA, which itself did not affect CYP27B1 expression, rescued CYP27B1 from transcriptional inhibition by genistein. In conclusion, our data argue for the use of genistein to resensitize prostate cancer cells to 1,25-D3; the addition of TSA may preserve the ability of these cells to synthesize 1,25-D3.
Farhan
Hesso
H
Department of Pathophysiology, University of Vienna Medical School, Vienna, Austria. hesso.farhan@univie.ac.at
Cross
Heide S
HS
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D065668:Vitamin D3 24-Hydroxylase
D016588:Anticarcinogenic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D019833:Genistein; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol