期刊
ONCOGENE
卷 23, 期 30, 页码 5175-5184出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1207654
关键词
androgen receptor; suppressor element; androgen-independent prostate cancer
资金
- NCI NIH HHS [CA9813501, CA-40758] Funding Source: Medline
Androgen receptor (AR) overexpression is one of the characteristics of prostate cancer ( PC) that progresses to hormone independence. An androgen-independent ( AI) derivative, with much higher AR-mRNAand protein levels than the parental LNCaP cell line, whose proliferation was androgen dependent ( AD), was used to explore the mechanism of AR overexpression. We found that a suppressor element (ARS), previously identified in mouse AR and located in the 5'-untranslated region of human AR gene, malfunctions in AI cells. Transfection of constructs that included ARS element into AD cells reduced the transactivating activities of both AR promoter and a heterologous SV40 promoter. The deletion of ARS resulted in an eightfold increase in AR-promoter activity in AD cells, but had no effect in AI cells. Moreover, the nuclear extracts of AD cells contained proteins that produced a specific, ARS-binding complex, while this complex appeared to have been lost from AI cells. Most importantly, treatment of AI cells with a demethylating agent or histone deacetylase inhibitors restored the lost ARS-binding complex. The restoration of the complex coincided with a reduced expression of AR-mRNA and protein and a reduced rate of AR-gene transcription, determined by nuclear run-on experiment. Thus, epigenetic transcriptional silencing of the suppressor protein(s) may be responsible for AR overexpression in AI cells, and its reversal in hormone-independent PC may normalize AR levels and restore their hormone dependence.
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