Nuclear receptors and pioneer factors drive the development and progression of
prostate cancer. In this disease, aggressive disease phenotypes and
hormone therapy failures result from resurgent activity of
androgen receptor (AR) and the upregulation of coactivator
protein p300 and pioneer factors (e.g., GATA2 and FOXA1). Thus, a major emphasis in the field is to identify mechanisms by which castrate-resistant AR activity and pioneer factor function can be combinatorially suppressed. Here we show that the turmeric spice
isoflavone curcumin suppresses p300 and CBP occupancy at sites of AR function.
Curcumin reduced the association of
histone acetylation and pioneer factors, thereby suppressing AR residence and downstream target gene expression.
Histone deacetylase inhibitors reversed the effects of
curcumin on AR activity, further underscoring the impact of
curcumin on altering the
chromatin landscape. These functions precluded pioneer factor occupancy, leading ultimately to a suppression of
ligand-dependent and
ligand-independent AR residence on
chromatin. Moreover, these functions were conserved even in cells with heightened pioneer factor activity, thus identifying a potential strategy to manage this subclass of
tumors.
Biological relevance was further identified using in vivo xenograft models mimicking
disease progression.
Curcumin cooperated in vivo with
androgen deprivation as indicated by a reduction in
tumor growth and delay to the onset of castrate-resistant disease. Together, our results show the combinatorial impact of targeting AR and
histone modification in
prostate cancer, thus setting the stage for further development of
curcumin as a novel agent to target AR signaling.