Charles Sawyers M.D., is past president of the American Society of Clinical Investigation, served on the National Cancer Institute's Board of Scientific Councilors, and is a member of the Institute of Medicine, National Academy of Sciences. In 2009, he was awarded the Lasker-Debakey Prize for Clinical Medical Research.
A summary of the February 2009 article by Dr. Sawyers in Cancer Research is available below:
Histone Deacetylases are Required for Androgen Receptor Function in Hormone-Sensitive and Castrate-Resistant Prostate Cancer
Derek S. Welsbie, Jin Xu, Yu Chen, Laetitia Borsu, Howard I. Scher, Neal Rosen, and Charles L. Sawyers
Cancer Res. 2009 69(3): 958-966
Current hormone therapies such as androgen receptor (AR) antagonists eventually fail, leading to a lethal drug-resistant stage called castration-resistant prostate cancer. Sawyers and colleagues have previously shown that the transition from castration-sensitive to castration-resistant disease is associated with the over-expression of AR protein. Agonists promote the recruitment of AR and coactivators that have histone acetyltransferase activity to promoters of AR target genes, leading to histone acetylase and active transcription of AR target genes. Antagonists promote the recruitment of corepressors that complex with histone deacetylases (HDACs) and repress gene expression.
In this article published in Cancer Research, Sawyers and colleagues examine the effect of HDAC inhibitors on AR function. They show that HDAC inhibitors, including SAHA (vorinostat) and LBH589, which are currently being tested in the clinic, decrease AR protein levels. Furthermore, HDAC inhibitors block AR transcriptional activity independent of AR protein levels, resulting in the inhibition of various AR-mediated genes including the TMPRSS2 gene involved in fusion with ETS family members in a majority of prostate cancers. These HDAC inhibitors are also able to inhibit AR activity in castration-resistant prostate cancer models. These data show that HDACs are required for AR transcriptional activity, suggesting HDAC inhibitors as potential therapeutics for the treatment of drug-resistant prostate cancer.
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