Prolonged androgen receptor loading onto chromatin and the efficient recruitment of p160 coactivators contribute to androgen-independent growth of prostate cancer cells

Department of Urology, University of California, Davis, School of Medicine, Sacramento, California 95817, USA.
The Prostate (Impact Factor: 3.57). 12/2008; 68(16):1816-26. DOI: 10.1002/pros.20849
Source: PubMed


Growth of most ablation-resistant prostate cancers (CaPs) is dependent on androgen receptor (AR) activity in chromatin, but cancer cells in these tumors have acquired altered AR activation. It is unclear how the aberrantly activated AR loads onto regulatory regions of AR-targeted genes. The purpose of this study was to assess the AR chromatin loading in an androgen-depleted environment.
The expression of PSA in androgen-resistant CaP cells was determined using RT-PCR and Western blot analysis. In order to investigate the binding of the AR to the PSA gene regulatory regions, chromatin immunoprecipitation (ChIP) was performed in the androgen-independent cds2 cell line in the presence or absence of androgens. In addition, we examined the involvement of p160 coactivators in the chromatin loading of the AR.
It was found that constitutive activation of PSA expression was the result of sustained occupancy by the AR at the regulatory region of this gene. This stable AR loading was not blocked by the AR antagonist bicalutamide. Furthermore, androgen-resistant CaP cells highly expressed both AR and the p160 coactivators and the AR was able to recruit TIF2. Downregulation of TIF2 using short hairpin RNA disrupted the AR loading to the PSA enhancer and subsequently inhibited AR activity.
Prolonged AR localization to the regulatory regions of AR targeted genes and the recruitment of p160 coactivators are a potential mechanism leading to androgen-independent activation of the AR. Disruption of AR chromatin loading could therefore become an important therapeutic target for this disease.

7 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chromosomal aberrations involving genes encoding members of the p160/SRC transcriptional coactivator family such as AIB1/ACTR and TIF2 implicated the coactivators in malignancy of human cells. Significant progress has been made in the last decade toward uncovering their roles in the development and progression of solid tissue tumors as well as leukemia and understanding of the underlying molecular mechanisms. Here, we review their genetic aberrations and dysregulation in expression in breast cancer, prostate cancer, and other nonhormone-responsive cancers. The experimental evidence gathered from studies using cell culture and animal models strongly supports a critical and, in some circumstances, their oncogenic function. We summarize results that the SRCs may contribute to tumorigenesis and disease progression through transcription factors such as E2F, PEA3, and AP-1 and through an intimate control of signaling pathways of growth factors-Akt and the receptor tyrosine kinases. The finding that a recently identified nuclear receptor coregulator ANCCA, like the SRCs, is frequently overexpressed in many types of cancers again underscores their broader roles in cancer.
    Progress in molecular biology and translational science 01/2009; 87:261-98. DOI:10.1016/S1877-1173(09)87008-7 · 3.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sex steroids, through their receptors, have potent effects on the signal pathways involved in osteogenic or myogenic differentiation. However, a considerable segment of those signal pathways has a prominent role in epithelial neoplastic transformation. The capability to intervene locally has focused on specific ligands for the receptors. Nevertheless, many signals are mapped to interactions of steroid receptor motifs with heterologous regulatory proteins. Some of those proteins interact with the glucocorticoid receptor and other factors essential to cell fate. Interactions of steroid receptor domain motifs with heterologous proteins affect specific target pathways; consequently, manipulation of specified protein modules complexed with steroid receptors may be a next major step for enhancing molecular targeted therapeutics. In the future, intervention at specific sections of receptor primary sequence may prove therapeutically more efficient in targeting pathways of choice than ligand selectivity can be.
    BioEssays 06/2009; 31(6):629-41. DOI:10.1002/bies.200800138 · 4.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There are currently few successful therapies for castration-resistant prostate cancer (CRPC). CRPC is thought to result from augmented activation of the androgen/androgen receptor (AR) signaling pathway, which could be enhanced by AR cofactors. In this study, peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) was found to be an AR cofactor. PGC-1alpha interacted with the N-terminal domain of AR, was involved in the N- and C-terminal interaction of AR, and enhanced the DNA-binding ability of AR to androgen-responsive elements in the prostate-specific antigen enhancer and promoter regions to increase the transcription of AR target genes. Silencing of PGC-1alpha suppressed cell growth of AR-expressing prostate cancer (PCa) cells by inducing cell-cycle arrest at the G(1) phase, similar to inhibition of androgen/AR signaling. Furthermore, PGC-1alpha knock-down also suppressed cell growth in the castration-resistant LNCaP-derivatives. These findings indicate that PGC-1alpha is involved in the proliferation of AR-expressing PCa cells by acting as an AR coactivator. Modulation of PGC-1alpha expression or function may offer a useful strategy for developing novel therapeutics for PCa, including CRPC, which depends on AR signaling by overexpressing AR and its coactivators.
    Molecular Endocrinology 01/2010; 24(1):114-127. DOI:10.1210/me.2009-0302 · 4.02 Impact Factor
Show more