Locus-wide chromatin remodeling and enhanced androgen receptor-mediated transcription in recurrent prostate tumor cells

被引:56
作者
Jia, Li
Shen, Howard C.
Wantroba, Marcus
Khalid, Omar
Liang, Gangning
Wang, Qingcai
Gentzschein, Elisabet
Pinski, Jacek K.
Stanczyk, Frank Z.
Jones, Peter A.
Coetzee, Gerhard A. [1 ]
机构
[1] USC Keck Sch Med, Norris Canc Ctr, Dept Urol, Los Angeles, CA USA
[2] USC Keck Sch Med, Norris Canc Ctr, Dept Prevent Med, Los Angeles, CA USA
[3] USC Keck Sch Med, Norris Canc Ctr, Div Med Oncol, Los Angeles, CA USA
[4] USC Keck Sch Med, Norris Canc Ctr, Dept Obstet & Gynecol, Los Angeles, CA USA
关键词
D O I
10.1128/MCB.00581-06
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 [生物化学与分子生物学]; 081704 [应用化学];
摘要
Prostate cancers (PCas) become resistant to hormone withdrawal through increased androgen receptor (AR) signaling. Here we show increased AR-mediated transcription efficiency in PCa cells that have acquired the ability to grow in low concentrations of androgen. Compared to androgen-dependent PCa cells, these cells showed increased activity of transiently transfected reporters and increased mRNA synthesis relative to levels of AR occupancy of the prostate-specific antigen (PSA) gene. The locus also displayed up to 10-fold-higher levels of histone H3-K9/K14 acetylation and H3-K4 methylation across the entire body of the gene. Although similar increased mRNA expression and locus-wide histone acetylation were also observed at another kallikrein locus (KLK2), at a third AR target locus (TMPRSS2) increased gene expression and locus-wide histone acetylation were not seen in the absence of ligand. Androgen-independent PCa cells have thus evolved three distinctive alterations in AR-mediated transcription. First, increased RNA polymerase initiation and processivity contributed to increased gene expression. Second, AR signaling was more sensitive to ligand. Third, locus-wide chromatin remodeling conducive to the increased gene expression in the absence of ligand was apparent and depended on sustained AR activity. Therefore, increased AR ligand sensitivity as well as locus-specific chromatin alterations contribute to basal gene expression of a subpopulation of specific AR target genes in androgen-independent PCa cells. These features contribute to the androgen-independent phenotype of these cells.
引用
收藏
页码:7331 / 7341
页数:11
相关论文
共 47 条
[1]
Androgen receptor as a target in androgen-independent prostate cancer - Discussion [J].
Sartor, O ;
Balk, SP ;
Brown, M .
UROLOGY, 2002, 60 (3A) :138-139
[2]
Genomic maps and comparative analysis of histone modifications in human and mouse [J].
Bernstein, BE ;
Kamal, M ;
Lindblad-Toh, K ;
Bekiranov, S ;
Bailey, DK ;
Huebert, DJ ;
McMahon, S ;
Karlsson, EK ;
Kulbokas, EJ ;
Gingeras, TR ;
Schreiber, SL ;
Lander, ES .
CELL, 2005, 120 (02) :169-181
[3]
The emerging roles of human tissue kallikreins in cancer [J].
Borgoño, CA ;
Diamandis, EP .
NATURE REVIEWS CANCER, 2004, 4 (11) :876-890
[4]
Contribution of the androgen receptor to prostate cancer predisposition and progression [J].
Buchanan, G ;
Irvine, RA ;
Coetzee, GA ;
Tilley, WD .
CANCER AND METASTASIS REVIEWS, 2001, 20 (3-4) :207-223
[5]
Molecular determinants of resistance to antiandrogen therapy [J].
Chen, CD ;
Welsbie, DS ;
Tran, C ;
Baek, SH ;
Chen, R ;
Vessella, R ;
Rosenfeld, MG ;
Sawyers, CL .
NATURE MEDICINE, 2004, 10 (01) :33-39
[6]
How does the histone code work? [J].
Cosgrove, MS ;
Wolberger, C .
BIOCHEMISTRY AND CELL BIOLOGY, 2005, 83 (04) :468-476
[7]
Mechanisms of androgen-refractory prostate cancer. [J].
Debes, JD ;
Tindall, DJ .
NEW ENGLAND JOURNAL OF MEDICINE, 2004, 351 (15) :1488-1490
[8]
Regulation of androgen receptor signaling in prostate cancer [J].
Dehm, SM ;
Tindall, DJ .
EXPERT REVIEW OF ANTICANCER THERAPY, 2005, 5 (01) :63-74
[9]
Dissociation between androgen responsiveness for malignant growth vs. expression of prostate specific differentiation markers PSA, hK2, and PSMA in human prostate cancer models [J].
Denmeade, SR ;
Sokoll, LJ ;
Dalrymple, S ;
Rosen, DM ;
Gady, AM ;
Bruzek, D ;
Ricklis, RM ;
Isaacs, JT .
PROSTATE, 2003, 54 (04) :249-257
[10]
Rush hour at the promoter: How the ubiquitin-proteasome pathway polices the traffic flow of nuclear receptor-dependent transcription [J].
Dennis, AP ;
O'Malley, BW .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2005, 93 (2-5) :139-151