Abstract A084: Reprogramming of androgen receptor gene expression by ACK1/TNK2 mediated histone H4 Tyr88-phosphorylation promotes castration resistance

Aberrant androgen receptor (AR) transcriptional co-activator activity underlies the onset and progression of prostate cancer (PC) to castration-resistant (CRPC) state. While anti-androgens provide immediate palliative benefits by negating AR transcriptional activity, resistance inevitably develops—either by AR gene amplification, mutation, or expression of splice variants, such as AR-V7. To achieve complete remission, ablation of AR expression appears to be the key. However, targeted inhibition of AR and AR-V7 gene expression with small-molecule inhibitors has not yet been accomplished. Recently, we uncovered a novel chromatin-regulated mechanism of AR transcriptional regulation mediated by the tyrosine kinase ACK1 (also known as TNK2). We observed that ACK1 phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex is read by H4-Y88-phosphorylation and in turn deposits the transcriptionally activating H3K4-trimethyl marks, promoting AR transcription in androgen-deficient environment. 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. Interestingly, we observed that AR itself was modified by acetylation at Lys609 residue in enzalutamide-resistant PC cells, revealing an additional mechanisms underlying castration resistance. Overall, these data reveal previously undocumented epigenetic circuitry that not only sustains AR and AR-V7 expression, but also provides mechanistic insight into rapid acquisition of resistance to antiandrogens. Citation Format: Nupam Mahajan, Kiran Mahajan, Harshani Lawrence, Nicholas Lawrence. Reprogramming of androgen receptor gene expression by ACK1/TNK2 mediated histone H4 Tyr88-phosphorylation promotes castration resistance [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A084.