CHD8, A Novel Beta-Catenin Associated Chromatin Remodeling Enzyme, Regulates Androgen Receptor Mediated Gene Transcription

2009 ◽  
Author(s):  
Daniel A. Bochar
Keyword(s):  
Androgen Receptor ◽  
Chromatin Remodeling ◽  
Gene Transcription ◽  
Beta Catenin

scholarly journals CHD8 Is an ATP-Dependent Chromatin Remodeling Factor That Regulates β-Catenin Target Genes

2008 ◽  
Vol 28 (12) ◽  
pp. 3894-3904 ◽  
Author(s):  
Brandi A. Thompson ◽  
Véronique Tremblay ◽  
Grace Lin ◽  
Daniel A. Bochar
Keyword(s):  
Gene Expression ◽  
Rna Interference ◽  
Chromatin Remodeling ◽  
Gene Transcription ◽  
Chromatin Structure ◽  
Target Genes ◽  
Promoter Regions ◽  
Hairpin Rna ◽  
Short Hairpin ◽  
Targeted Gene Expression

ABSTRACT ATP-dependent chromatin remodeling by the CHD family of proteins plays an important role in the regulation of gene transcription. Here we report that full-length CHD8 interacts directly with β-catenin and that CHD8 is also recruited specifically to the promoter regions of several β-catenin-responsive genes. Our results indicate that CHD8 negatively regulates β-catenin-targeted gene expression, since short hairpin RNA against CHD8 results in the activation of several β-catenin target genes. This regulation is also conserved through evolution; RNA interference against kismet, the apparent Drosophila ortholog of CHD8, results in a similar activation of β-catenin target genes. We also report the first demonstration of chromatin remodeling activity for a member of the CHD6-9 family of proteins, suggesting that CHD8 functions in transcription through the ATP-dependent modulation of chromatin structure.

Dual targeting of the androgen receptor and hypoxia-inducible factor-1α pathways to synergistically inhibit castrate-resistant prostate cancer.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 270-270
Author(s):  
William Douglas Figg ◽  
Elena V. Fernandez ◽  
Kelie M Reece ◽  
Ariel M Ley ◽  
Sarah M Troutman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Cancer Cell ◽  
Gene Transcription ◽  
Prostate Cancer Cell ◽  
Gene Expressions ◽  
Dual Targeting ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

270 Background: Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). While enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and HIF-1α are key regulators of these processes, dual targeting of both signaling axis represents an attractive therapeutic approach. Methods: Crosstalk of the AR and HIF-1α signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. Cells were stimulated with dihydrotestosterone (DHT) or the hypoxia mimetic cobalt chloride. HIF-1α inhibition was achieved by siRNA silencing HIF-1α or via chetomin, a disruptor of HIF-1α-p300 interactions. Results: In prostate cancer cells, gene expressions of AR targets (KLK3, FKBP5, TMPRSS2) were repressed by HIF-signaling; conversely, HIF-1α target expressions (VEGF, ENO1, LDHA) were induced by DHT-mediated AR signaling. Treatment of CRPC cells with enzalutamide and chetomin or HIF-1α siRNA attenuated AR-regulated and HIF-1α-mediated gene transcription. The combination of enzalutamide and HIF-1α inhibition was more effective than either treatment alone. Similarly, the combination also reduced VEGF protein levels. HIF-1α siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells. Additionally, HIF-1α siRNA synergistically increased enzalutamide-induced apoptosis. Conclusions: Combination of enzalutamide with HIF-1α inhibition resulted in synergistic inhibition of AR-dependent and gene specific HIF-dependent expression, prostate cancer cell growth, and apoptosis.

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