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.

中文翻译：

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ACK1 / TNK2调节去势抵抗性前列腺癌中的组蛋白H4 Tyr88磷酸化和AR基因表达。

雄激素受体（AR）对于前列腺癌发展为去势抵抗（CRPC）状态至关重要。AR拮抗剂由于不能抑制AR或其剪接变体AR-V7的表达而无效。在这里，我们报告酪氨酸激酶ACK1（TNK2）磷酸化AR转录起始位点上游酪氨酸88处的组蛋白H4。WDR5 / MLL2复合物读取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敏感的幼稚和enzalutamide耐药前列腺癌细胞逆转pY88-H4表观遗传标记，并降低AR和AR-V7水平以减轻CRPC肿瘤的生长。因此，