Locus-Wide Chromatin Remodeling and Enhanced Androgen Receptor-Mediated Transcription in Recurrent Prostate Tumor Cells

ABSTRACT 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.

[1]  Arul M Chinnaiyan,et al.  TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. , 2006, Cancer research.

[2]  Carlos Caldas,et al.  Chromatin modifier enzymes, the histone code and cancer. , 2005, European journal of cancer.

[3]  J. Tchinda,et al.  Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer , 2005, Science.

[4]  F. Lan,et al.  Regulation of LSD1 histone demethylase activity by its associated factors. , 2005, Molecular cell.

[5]  S. Henikoff,et al.  Genome-scale profiling of histone H3.3 replacement patterns , 2005, Nature Genetics.

[6]  G. Coetzee,et al.  Androgen receptor-dependent PSA expression in androgen-independent prostate cancer cells does not involve androgen receptor occupancy of the PSA locus. , 2005, Cancer research.

[7]  C. Wolberger,et al.  How does the histone code work? , 2005, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[8]  D. Jackson,et al.  The amazing complexity of transcription factories. , 2005, Briefings in functional genomics & proteomics.

[9]  S. Horvath,et al.  Global histone modification patterns predict risk of prostate cancer recurrence , 2005, Nature.

[10]  Kevin Struhl,et al.  Distinction and relationship between elongation rate and processivity of RNA polymerase II in vivo. , 2005, Molecular cell.

[11]  Keji Zhao,et al.  Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping. , 2005, Genes & development.

[12]  B. O’Malley,et al.  Rush hour at the promoter: How the ubiquitin-proteasome pathway polices the traffic flow of nuclear receptor-dependent transcription , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[13]  G. Coetzee,et al.  The role of protein kinase A pathway and cAMP responsive element-binding protein in androgen receptor-mediated transcription at the prostate-specific antigen locus. , 2005, Journal of molecular endocrinology.

[14]  Eric S. Lander,et al.  Genomic Maps and Comparative Analysis of Histone Modifications in Human and Mouse , 2005, Cell.

[15]  Michael Ittmann,et al.  Mutation of the androgen receptor causes oncogenic transformation of the prostate. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[16]  D. Tindall,et al.  Regulation of androgen receptor signaling in prostate cancer , 2005, Expert review of anticancer therapy.

[17]  S. Kato,et al.  A Role of Androgen Receptor Protein in Cell Growth of an Androgen-Independent Prostate Cancer Cell Line , 2005, Bioscience, biotechnology, and biochemistry.

[18]  Yang Shi,et al.  Histone Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1 , 2004, Cell.

[19]  E. Diamandis,et al.  The emerging roles of human tissue kallikreins in cancer , 2004, Nature Reviews Cancer.

[20]  D. Tindall,et al.  Mechanisms of androgen-refractory prostate cancer. , 2004, The New England journal of medicine.

[21]  W. Gerald,et al.  Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer. , 2004, Endocrine-related cancer.

[22]  David Landsman,et al.  High-resolution genome-wide mapping of histone modifications , 2004, Nature Biotechnology.

[23]  Peter A. Jones,et al.  Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[24]  A. Dean,et al.  Developmental stage differences in chromatin subdomains of the β-globin locus , 2004 .

[25]  Thomas Kodadek,et al.  Physical and functional association of RNA polymerase II and the proteasome. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  G. Coetzee,et al.  Dynamic methylation of histone H3 at lysine 4 in transcriptional regulation by the androgen receptor. , 2003, Nucleic acids research.

[27]  G. Coetzee,et al.  Androgen receptor activity at the prostate specific antigen locus: steroidal and non-steroidal mechanisms. , 2003, Molecular cancer research : MCR.

[28]  L. Sokoll,et al.  Dissociation between androgen responsiveness for malignant growth vs. expression of prostate specific differentiation markers PSA, hK2, and PSMA in human prostate cancer models , 2003, The Prostate.

[29]  J. Ellenberg,et al.  Cyclic, proteasome-mediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling. , 2003, Molecular cell.

[30]  Wei Xu,et al.  Androgen-induced recruitment of RNA polymerase II to a nuclear receptor–p160 coactivator complex , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  O. Jänne,et al.  Involvement of Proteasome in the Dynamic Assembly of the Androgen Receptor Transcription Complex* , 2002, The Journal of Biological Chemistry.

[32]  Toshiki Mori,et al.  ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. , 2002, Molecular cell.

[33]  S. Balk,et al.  Androgen receptor as a target in androgen-independent prostate cancer. , 2002, Urology.

[34]  D. DeFranco,et al.  Proteasomal Inhibition Enhances Glucocorticoid Receptor Transactivation and Alters Its Subnuclear Trafficking , 2002, Molecular and Cellular Biology.

[35]  Ricky W. Johnstone,et al.  Histone-deacetylase inhibitors: novel drugs for the treatment of cancer , 2002, Nature Reviews Drug Discovery.

[36]  D. Tindall,et al.  Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells. , 2002, Cancer research.

[37]  D. Feldman,et al.  The development of androgen-independent prostate cancer , 2001, Nature Reviews Cancer.

[38]  D. Reinberg,et al.  Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. , 2001, Genes & development.

[39]  C. Allis,et al.  The language of covalent histone modifications , 2000, Nature.

[40]  A. Goldberg,et al.  Proteasome inhibitors: valuable new tools for cell biologists. , 1998, Trends in cell biology.

[41]  L. Chung,et al.  Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. , 1994, Cancer research.

[42]  G. Jenster,et al.  The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens , 1992, The Journal of Steroid Biochemistry and Molecular Biology.

[43]  D. Mishell,et al.  Serum testosterone concentrations in women throughout the menstrual cycle and following HCG administration. , 1974, American journal of obstetrics and gynecology.

[44]  A. Dean,et al.  Developmental stage differences in chromatin subdomains of the beta-globin locus. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[45]  R. Vessella,et al.  Molecular determinants of resistance to antiandrogen therapy , 2004, Nature Medicine.

[46]  G. Coetzee,et al.  Contribution of the Androgen Receptor to Prostate Cancer Predisposition and Progression , 2004, Cancer and Metastasis Reviews.

[47]  Desok Kim,et al.  Androgen receptor expression and cellular proliferation during transition from androgen-dependent to recurrent growth after castration in the CWR22 prostate cancer xenograft. , 2002, The American journal of pathology.