Staverosky JA, Zhu XH, Ha S, Logan SK
Chronic inflammation has been linked to cancer initiation and progression in a variety of tissues, yet the impact of acute and chronic inflammatory signaling on androgen receptor function has not been widely studied. In this report, we examine the impact of the inflammation-linked cytokine, interleukin-1β on androgen receptor function in prostate cancer cells. We demonstrate that acute interleukin-1β treatment inhibits the transcription of the androgen receptor gene itself, resulting in the reduction of androgen receptor protein levels. Interestingly, in cells subjected to chronic interleukin-1β stimulation, the transcription of the androgen receptor gene is restored within a few cell passages and the cells acquire the ability to grow in the presence of the anti-androgen, bicalutamide. Importantly, the changes that accompany this loss of androgen receptor regulation and gain of anti- androgen resistance are stably heritable since once established, the phenotype is maintained even in the absence of exogenously added interleukin-1β. Further, bicalutamide resistance correlates with increased transcription of androgen receptor target genes and histone H3K4 dimethylation at M-phase gene enhancers. Overall, our studies demonstrate a novel route to anti-androgen resistance upon exposure to an inflammatory cytokine and provide a new tool to further understand how anti-androgen resistance emerges under chronic inflammation.