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Tumor and Stem Cell Biology

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

Supriya Shah, Shikha Prasad and Karen E. Knudsen
Supriya Shah
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Shikha Prasad
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Karen E. Knudsen
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DOI: 10.1158/0008-5472.CAN-11-0943 Published March 2012
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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 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. Cancer Res; 72(5); 1248–59. ©2012 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received March 21, 2011.
  • Revision received December 28, 2011.
  • Accepted January 10, 2012.
  • ©2012 American Association for Cancer Research.
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Cancer Research: 72 (5)
March 2012
Volume 72, Issue 5
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Targeting Pioneering Factor and Hormone Receptor Cooperative Pathways to Suppress Tumor Progression
Supriya Shah, Shikha Prasad and Karen E. Knudsen
Cancer Res March 1 2012 (72) (5) 1248-1259; DOI: 10.1158/0008-5472.CAN-11-0943

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Targeting Pioneering Factor and Hormone Receptor Cooperative Pathways to Suppress Tumor Progression
Supriya Shah, Shikha Prasad and Karen E. Knudsen
Cancer Res March 1 2012 (72) (5) 1248-1259; DOI: 10.1158/0008-5472.CAN-11-0943
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