The androgen receptor (AR) is a ligand-dependent transcription factor that plays a key role in the development and function of the prostate gland; alterations of AR function are associated with prostate cancer. With the goal of identifying new regulators of AR function, this model makes use of the DRSC 2.0 whole genome RNAi library for use with Drosophila cell culture. The activity of the AR-dependent transcription pathway was measured by reporter gene activity in Drosophila S2 cells upon stimulation with the synthetic androgen R1881.
The primary goal of the screen was to identify positive regulators that when reduced, decreased AR activity. Initially, 21 AR-specific activators were identified, including several for which the human orthologs are known regulators. Two genes not previously associated with AR regulation were characterized further: Dmel\MED19 (orthologous to human MED19) and Dmel\Hipk (orthologous to human HIPK1, HIPK2, HIPK3).
Experiments in human cells extended findings in the fly system. Inhibition of MED19 or HIPK2 modulates AR-dependent gene expression and selectively reduces the proliferation of AR-expressing prostate cancer cells. These findings provide additional targets for development of drugs effective against prostate cancers that have developed resistance to androgen deprivation therapies.
In several Drosophila models, elevated levels of Dmel\Hipk have been shown to induce hyperplasia; see the human disease model report 'cancer, multiple, HIPK-related' (FBhh0000776).
[updated Dec. 2020 by FlyBase; FBrf0222196]
Alterations of androgen receptor (AR) function are associated with prostate cancer (Tan et al, 2014; pubmed:24909511; Fujita and Nonomura, 2019; pubmed:30209899).
Androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years (Tan et al, 2014; pubmed:24909511; Fujita and Nonomura, 2019; pubmed:30209899).
