Agonist and antagonist switch DNA motifs recognized by human androgen receptor in prostate cancer

Abstract

Human transcription factors recognize specific DNA sequence motifs to regulate transcription. It is unknown whether a single transcription factor is able to bind to distinctly different motifs on chromatin, and if so, what determines the usage of specific motifs. By using a motif-resolution chromatin immunoprecipitationexonuclease (ChIP-exo) approach, we find that agonist-liganded human androgen receptor (AR) and antagonist-liganded AR bind to two distinctly different motifs, leading to distinct transcriptional outcomes in prostate cancer cells. Further analysis on clinical prostate tissues reveals that the binding of AR to these two distinct motifs is involved in prostate carcinogenesis. Together, these results suggest that unique ligands may switch DNA motifs recognized by ligand-dependent transcription factors in vivo. Our findings also provide a broad mechanistic foundation for understanding ligand-specific induction of gene expression profiles.

Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression

“…In contrast MDV3100 bound AR does not bind to the DNA and thus the elimination of NCOR1 should have little or no effect on AR dependent activity under these conditions whereas AR independent actions would be retained. Recently, MDV3100 regulated changes in gene expression have been reported for LNCaP (36). A comparison of MDV3100 transcriptional regulation (GSE44905 and GSE44924) in LNCaP and bicalutamide dependent changes in our experiments showed that approximately 20% of the genes were regulated by both ligands.…”

Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes

“…Native MNase ChIP-seq was performed as we descried previously 46 with modifications. For tissue H3K4me3 ChIP-seq, the frozen tissues (50–100 mg), purchased from Cureline, were trimmed and chopped into small pieces on ice, and then washed with ice cold PBS twice.…”

“…The cells were maintained in 10% fetal calf serum (FCS)-supplemented DMEM medium. Cell proliferation assays were performed as we described previously 46,47 with modifications. For WST-1 assays, cells were seeded (2×10 3 cells/well for A549, 4×10 3 cells/well for MCF7 and 8×10 3 cells/well for HepG2 cells) in 96-well plates in triplicates 24 h before transfection.…”

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

“…This has highlighted the importance of studying AR genomic binding in primary cells or tissues. Therefore, more recently, the genomic behavior of AR has been investigated in prostate cancer tissues and has revealed that AR genomic binding and interactions are reprogrammed with different tumour stages and have prognostic value [30][31][32][33]. However, tissue samples typically contain multiple distinct cellular components and the majority of studies to date have neglected the role of the AR in CAFs present in the tumour microenvironment.…”