期刊
CANCER CELL
卷 31, 期 6, 页码 790-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2017.05.003
关键词
-
资金
- NIH/NCI [5R01CA135328]
- Department of Defense [W81XWH-14-1-0002, W81XWH-14-1-0003, W81XWH-15-1-0312, W81XWH-12-1-0248, W81XWH-14-1-0251, W81XWH-15-1-0059]
- Bankhead-Coley [6BC08]
- Miles-for-Moffitt Award [09-33661-15-13]
- Core Facilities at Moffitt Cancer Center
- Cancer Center Support Grant [P30 CA076292]
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 up-stream 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据