Targeting Pioneering Factor and Hormone Receptor Cooperative Pathways to Suppress Tumor Progression

Abstract

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 current 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 illustrated by a reduction in tumor growth and delay to the onset of castrate-resistant disease. Together, our results demonstrate the combinatorial impact of targeting AR and histone modification in prostate cancer, setting the stage for further development of curcumin as a novel agent to target AR signaling.

Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism

“…In particular, restricted histone acetylation has been shown to inhibit the accessibility of chromatin to the AR by attenuating recruitment of the pioneering factor GATA2 [39]. The AR itself is also acetylated, a modification that increases its stability [73].…”

“…Similarly, acetyl-CoA promotes global histone acetylation and expression of pro-proliferative gene expression in cancer cells [15, 17, 38], although the underlying mechanisms of gene regulation by acetyl-CoA are not fully clear. Histone acetylation has been shown to be important for AR recruitment to chromatin and transcriptional activity [39]. Thus, elevated production of nuclear-cytoplasmic acetyl-CoA may support prostate tumor growth through both lipid metabolism and gene regulation.…”

Moving Beyond the Androgen Receptor (AR): Targeting AR-Interacting Proteins to Treat Prostate Cancer

“…Another well-studied agent for KAT inhibition is curcumin – which is notable as a component of the spice turmeric, and has been implicated as an anticancer agent for decades (141) . In vitro use of curcumin in prostate lines has resulted in decreased AR activity in both androgen-dependent as well as castration-resistant PCa cells (142) . Despite this, the ubiquitous expression of KATs such as CBP and p300, and their importance in normal tissue as well as cancer cells severely limit the therapeutic window in which to treat patients.…”

Impact of Epigenetic Dietary Components on Cancer through Histone Modifications

“…In vitro and in vivo studies on several prostate cancer cell lines conducted by Shah S et al suggested that curcumin suppressed p300 and CBP occupancy at androgen receptor (AR) functional sites by decreasing the association of histone acetylation and pioneer factors, which resulted in the inhibition of AR residence and downstream target gene expression. They further verified the role of curcumin as a HAT inhibitor by using HDAC inhibitors, finding that the effects of curcumin on AR activity were reversed [133]. Another study on the human prostate cancer cell line LNCaP indicated that although the total HDAC activity was suppressed upon treatment with curcumin probably due to the decrease of HDAC8 expression, the expression of HDAC1, HDAC4, HDAC5 and HDAC8 were increased [134].…”