Abstract 2378: Histone H4 tyr88-phosphorylation mediated by ACK1 promotes castration-resistant prostate cancer by epigenetic reprogramming of androgen receptor

Abstract

Abstract Androgen receptor (AR) plays a paramount role in the onset and progression of prostate cancer (PC). This very facet underlies androgen deprivation therapy (ADT), a preferred treatment to negate AR transcriptional activity. While ADT provides immediate palliative benefits, it is ineffective long term, as the recalcitrant disease recurs within 2-3 years and progresses to a lethal stage, referred to as the metastatic castration-resistant prostate cancer (mCRPC). The AR gene (AR) is amplified or mutated in >50% of mCRPCs, suggesting that PC cells may have reinvigorated AR transcription as a response to the loss of existing AR activity by ADT. Consequently, resistance to ADT has become one of the most vexing problems in PC therapy. AR antagonists are often ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. We developed a new class of ACK1 kinase-specific small molecule inhibitor (R)-9bMS that suppresses ACK1 kinase activity at IC50= 48 nM. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state. Citation Format: Nupam P. Mahajan, Kiran Mahajan, Nicholas Lawrence, Harshani Lawrence. Histone H4 tyr88-phosphorylation mediated by ACK1 promotes castration-resistant prostate cancer by epigenetic reprogramming of androgen receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2378.