Aberrant Chromatin Modification as a Mechanism of Prostate Cancer
Abstract
The purpose of this study was to test me hypothesis that aberrant chromatin modification plays a critical role in prostate cancer (CaP) progression. Scope of this study: We proposed to analyze histone acetylation and phosphorylation patterns on androgen receptor (AR) target genes such as PSA in malignant prostate cancer cells. Comparison of me patterns of histone modifications between different CaP cells will allow us to identify me chromatin modifications mat are altered during CaP progression and me responsible enzymatic activities. Major findings during the first two years: We began our study by examining histone modification such as acetylation on AR target gene PSA in the androgen dependent LNCaP cells and have made the following findings with the details incorporated in the attached paper published recently in PNAS and described below: A) Using chromatin immunoprecipitation (ChIP) assay as a measurement, we found that DHT induced marked histone hyperacetylation at both the promoter and me enhancer of PSA gene, while anti-androgens such as casodex induced histone hypoacetylation primarily at the enhancer elements. B) We also found mat DHT induced the recruitment/occupancy of nuclear receptor coactivators including members of the p160/SRC-1 family and CBP/p300, while casodex the recruitment/occupancy of histone deacetylases such as HDAC1 and HDAC2. These proteins are components of the nuclear receptor corepressor complexes. The p160 coactivators such as ACTR and SRC-1 and CBP/p300 proteins are demonstrated to possess histone acetylase (HAT) activities. C) We demonstrated mat elevation of ACTR protein level in the LNCaP cells not only increased DHT induction of PSA gene expression, but also induced androgen-independent PSA expression, suggesting the involvement of HAT protein ACTR in AR-mediated control of gene expression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2003
- Accession Number
- ADA417978
Entities
People
- Hongwu Chen
Organizations
- University of California