ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer

• DOI: 10.1016/j.ccell.2017.05.003
• Publication Date: 2017-06-12T22:45:44Z
• Authors: Kiran Mahajan; Pavani Malla; Harshani R. Lawrence; Zhihua Chen; Chandan Kumar-Sinha; Rohit Malik; Sudhanshu Shukla; Jongphil Kim; Domenico Coppola; Nicholas J. Lawrence; Nupam P. Mahajan
• Keywords: Male; Protein-Tyrosine Kinases; Epigenesis, Genetic; 3. Good health; Gene Expression Regulation, Neoplastic; Histones; Prostatic Neoplasms, Castration-Resistant; Drug Resistance, Neoplasm; Receptors, Androgen; Benzamides; Nitriles; Phenylthiohydantoin; Tumor Cells, Cultured; Humans; RNA, Messenger; Phosphorylation; Protein Kinase Inhibitors; Cell Proliferation

The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are 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. 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.