Mahajan Kiran, Malla Pavani, Lawrence Harshani R, Chen Zhihua, Kumar-Sinha Chandan, Malik Rohit, Shukla Sudhanshu, Kim Jongphil, Coppola Domenico, Lawrence Nicholas J, Mahajan Nupam P
Tumor Biology Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.
Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Cancer Cell. 2017 Jun 12;31(6):790-803.e8. doi: 10.1016/j.ccell.2017.05.003.
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.
雄激素受体（AR）对于前列腺癌进展至去势抵抗性（CRPC）状态至关重要。AR拮抗剂无效，因为它们无法抑制AR或其剪接变体AR-V7的表达。在此，我们报告酪氨酸激酶ACK1（TNK2）在AR转录起始位点上游的酪氨酸88处使组蛋白H4磷酸化。WDR5/MLL2复合物识别H4-Y88-磷酸化标记并沉积促进AR转录的转录激活H3K4-三甲基标记。ACK1抑制剂（R）-9bMS逆转pY88-H4表观遗传标记，使原发性和恩杂鲁胺耐药前列腺癌细胞敏感，并降低AR和AR-V7水平以减轻CRPC肿瘤生长。因此，前馈ACK1/pY88-H4/WDR5/MLL2/AR表观遗传回路驱动CRPC，并且对于维持恶性状态是必需的。
