Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 39, Pages 16663-16668Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0908908106
Keywords
HSP90; acetylation; ERG
Categories
Funding
- Flight Attendant Medical Research Institute and National Institutes of Health [1KL2 RR024141 01]
- National Center for Research Resources, a component of the National Institutes of Health (NIH) [UL1 RR024140]
- NIH Roadmap for Medical Research
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High consumption of cruciferous vegetables is associated with a reduced risk of prostate cancer in epidemiological studies. There is preliminary evidence that sulforaphane, derived from glucoraphanin found in a number of crucifers, may prevent and induce regression of prostate cancer and other malignancies in preclinical models, but the mechanisms that may explain these effects are not fully defined. Recent reports show that sulforaphane may impair prostate cancer growth through inhibition of histone deacetylases, which are up-regulated in cancer. Indeed, one of these enzymes, histone deacetylase 6 (HDAC6), influences the acetylation state of a key androgen receptor (AR) chaperone, HSP90. AR is the central signaling pathway in prostate cancer, and its inhibition is used for both prevention and treatment of this disease. However, it is not known whether the effects of sulforaphane involve suppression of AR. We hypothesized that sulforaphane treatment would lead to hyperacetylation of HSP90 and that this would destabilize AR and attenuate AR signaling. We confirmed this by demonstrating that sulforaphane enhances HSP90 acetylation, thereby inhibiting its association with AR. Moreover, AR is subsequently degraded in the proteasome, which leads to reduced AR target gene expression and reduced AR occupancy at its target genes. Finally, sulforaphane inhibits HDAC6 deacetylase activity, and the effects of sulforaphane on AR protein are abrogated by overexpression of HDAC6 and mimicked by HDAC6 siRNA. The inactivation by sulforaphane of HDAC6-mediated HSP90 deacetylation and consequent attenuation of AR signaling represents a newly defined mechanism that may help explain this agent's effects in prostate cancer.
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