1. ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.
- Author
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Mahajan K, Malla P, Lawrence HR, Chen Z, Kumar-Sinha C, Malik R, Shukla S, Kim J, Coppola D, Lawrence NJ, and Mahajan NP
- Subjects
- Benzamides, Cell Proliferation drug effects, Drug Resistance, Neoplasm, Epigenesis, Genetic, Humans, Male, Nitriles, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin therapeutic use, Phosphorylation, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases genetics, RNA, Messenger metabolism, Receptors, Androgen metabolism, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Histones metabolism, Prostatic Neoplasms, Castration-Resistant genetics, Protein-Tyrosine Kinases physiology, Receptors, Androgen genetics
- Abstract
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., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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