Abstract 87: Targeting androgen receptor acetylation as a treatment for castrate-resistant prostate cancer

Document Type

Article

Publication Date

2015

Abstract

The goal of our studies is to determine the potential of targeting androgen receptor (AR) acetylation as a means to counter androgen-independent prostate cancer (PCa). AR lysine residues 630/632/633 are acetylated in response to androgen-binding. This AR modification has been shown to enhance the transcriptional function of AR and to contribute to prostate tumorigenesis. These observations are supported by the discovery of an AR mutation that mimics this modification in a subset of prostate cancer patients (K630T), as well as increased levels of AR acetyltransferases in some advanced cases. We are specifically interested in the role of this modification in castrate-resistant prostate cancer, and we hypothesize that acetylation contributes to aberrant AR activation in castrate-resistant prostate cancer and possibly in androgen receptor antagonist resistant disease. We are utilizing genetic and pharmacological approaches to determine the function of AR acetylation in PCa, both in cell culture and in in vivo models. We have generated C4-2 cell lines within which we have stably knocked down endogenous AR (shRNA) and replaced it with acetylation-mutant AR (acetylation-null, acetylation-mimic, or lysine-intact controls). We have been performing growth and transcription assays to assess the effect of AR acetylation on these attributes of castrate-resistant PCa. Cells expressing acetylation-mimic AR have increased expression of select AR target gene transcripts, compared to cells expressing AR, null for acetylation. Enhanced AR transcriptional activity corresponds with a growth advantage of acetylation-mimic AR-expressing cells, whereas acetylation-null AR expressing cells undergo a substantial growth inhibition. Studies in mouse xenografts will further clarify whether AR acetylation is a driver of castrate-resistant disease and whether targeting AR acetylation is a rational strategy to treat this advanced disease state. Continued studies will also validate the potential of targeting AR acetylation as a means to combat AR antagonist resistant disease. The growth inhibition of cells expressing acetylation-null AR suggests that reducing AR acetylation may be a means to treat castrate-resistant PCa.

Publication Title

Cancer research

Volume

75

Issue

15 Supplement

First Page

87

Last Page

87

Comments

This article was published in Cancer research, Volume 75, Issue 15 Supplement, Pages 87-87.

The published version is available at http://dx.doi.org/10.1158/1538-7445.AM2015-87.

Copyright © 2015 AACR.

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