Cryptotanshinone down-regulates androgen receptor signaling by modulating lysine-specific demethylase 1 function.
Int J Cancer
; 131(6): 1423-34, 2012 Sep 15.
Article
en En
| MEDLINE
| ID: mdl-22052438
Development and progression of prostate cancer are intimately associated with androgen receptor (AR) signaling. The emergence of hormone-refractory prostate cancer and consequent failure of conventional androgen deprivation therapies make it necessary to bypass hormonal resistance by targeting the same signaling pathway at new intervention points. In our study, we showed that cryptotanshinone inhibited the growth of AR-positive prostate cancer cells, suggesting that cryptotanshinone affected AR function. Cryptotanshinone also profoundly inhibited the transcriptional activity of AR and suppressed the expression of several AR-target genes at the mRNA and the protein levels. At the molecular level, cryptotanshinone disrupted the interaction between AR and lysine-specific demethylase 1 (LSD1), and inhibited the complex of AR and LSD1 to the promoter of AR target genes without affecting the protein degradation and translocation of AR. Cryptotanshinone increased the mono-methyl and di-methylation of Histone H3 lysine 9 (H3K9), a repressive histone marker which is demethylated and activated by LSD1. These data suggest that cryptotanshinone functions via inhibition of LSD1, a protein that promotes AR-dependent transcriptional activity via derepression of H3K9. In summary, we describe a novel mechanism whereby cryptotanshinone down-regulates AR signaling via functional inhibition of LSD1-mediated demethylation of H3K9 and represses the transcriptional activity of AR. Our data suggest that cryptotanshinone can be developed as a potential therapeutic agent for prostate cancer.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenantrenos
/
Medicamentos Herbarios Chinos
/
Transducción de Señal
/
Receptores Androgénicos
/
Histona Demetilasas
Límite:
Humans
/
Male
Idioma:
En
Revista:
Int J Cancer
Año:
2012
Tipo del documento:
Article
País de afiliación:
Taiwán
Pais de publicación:
Estados Unidos