SAN FRANCISCO, CA USA (UroToday.com) - In this session, Christopher Evans, MD described some very recent and highly novel findings by his group relating to androgen receptor (AR) transcriptional activation mechanics.
His group has recently identified long noncoding RNAs (lncRNAs) which provide a scaffold to recruit components to the AR complex. The two lncRNAs, PRNCR1 and PCGEM1 are expressed in prostate cancer cells and increase tumorogenicity and growth in soft agar in pre-clinical models of the disease. Both lncRNAs are required for both ligand-dependent and -independent AR transactivation. PRNCR1 acts by recruiting a protein methyltransferase (DOT1L) to the complex which methylates AR itself. This methylation event is required for both PCGEM1 recruitment and AR-mediated transactivation. Interestingly, this DOT1L is druggable.
The second part of his talk centered on a highly novel method to identify genomic targets of small-molecule drugs which interact with chromatin, called drug-seq. The methodology uses a drug of interest, which is chemically modified to contain a linker molecule that contains biotin. Chromatin from the cells treated with the drug is then bathed in streptavidin, which will covalently bind to biotin. Streptavidin can then be collected and the genomic targets can be isolated and sequenced. This technique was used to probe a novel drug, SD70. Using this technique, SD70 was found to colocalize with AR at both ligand-dependent and independent transcriptional regulatory elements. Additionally, SD70 was found to target KDM4C, another histone lysine demthylase enzyme. This protein removes methyl groups from specific amino acid residues within the histone tail which when methylated repress transcription. Removing the methyl groups from histones at AR targets allows the target to be transcribed. This exciting finding again lends itself to novel drug developments that target AR independent of the hormonal axis.
Highlights of a presentation by Christopher P. Evans, MD at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
UC Davis Health System, Davis, CA USA