title: Androgen receptor level controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line.
abstract: 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-mRNA and 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.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Mount Sinai School of Medicine, Box 1129, 1 Gustave Levy Place, New York, NY 10029, USA.
authors.forename: Long G
authors.initials: LG
authors.lastname: Wang
authors.forename: Liliana
authors.initials: L
authors.lastname: Ossowski
authors.forename: Anna C
authors.initials: AC
authors.lastname: Ferrari
mesh_terms: D020121:5' Untranslated Regions; D002277:Carcinoma / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D020121:5' Untranslated Regions; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D011506:Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; C012589:trichostatin A; D008156:Luciferases