1. ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.
- Author
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Mahajan, Kiran, Malla, Pavani, Lawrence, Harshani R., Chen, Zhihua, Kumar-Sinha, Chandan, Malik, Rohit, Shukla, Sudhanshu, Kim, Jongphil, Coppola, Domenico, Lawrence, Nicholas J., and Mahajan, Nupam P.
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PROSTATE cancer & genetics , *GENE expression , *HISTONES , *CASTRATION , *EPIGENETICS - Abstract
Summary 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. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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