University of Wisconsin-Madison Madison United States
This proposal provides an unbiased identification of aberrant enzymatic activities and histone PTM states in the development of castrate-resist PCa CRPC. Using the peptide-microarray technology to obtain preliminary data, we found changes in hormone sensitive LNCaP and its castrate-resistant PCa clone CT-4 that identified several altered histone H3 acetyltransferases and deacetylases. We will apply this workflow t establish whether these enzymes are commonly dysregulated in other castrate-resistant PCa cell lines and in human PCa tissues, or whether distinct sets of epigenetic modifiers drive resistance in different patients. Based on these data we hypothesize that specific histone-modifying enzymes altered during the development of castrate-resistant PCa CRPC can be targeted therapeutically. We propose 3 Specific Aims 1. To identify dysregulated epigenetic enzymes in hormone-sensitive and CRPC, 2. To validate altered PTM states in human samples from hormone-sensitive and CRPC. 3. To provide proof-of-concept that CRPC is dependent on these aberrant enzyme activities and therefore responsive to small-molecules that target their activity. This novel study provides an unbiased identification of aberrant enzymatic activities and histone PTM states in CRPC. This understudied area in PCa is significant not only in identifying biomarkers for diagnosis and prognosis, but in providing a therapeutic strategy that targets epigenetic mechanisms.