@article{ecf20bedf3954ff28513959fb6c7c702,
title = "ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer",
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.",
keywords = "ACK1, AR, AR-V7, TNK2, castration resistance, enzalutamide, epigenetics, histone, prostate cancer, small-molecule inhibitor, tyrosine phosphorylation",
author = "Kiran Mahajan and Pavani Malla and Lawrence, {Harshani R.} and Zhihua Chen and Chandan Kumar-Sinha and Rohit Malik and Sudhanshu Shukla and Jongphil Kim and Domenico Coppola and Lawrence, {Nicholas J.} and Mahajan, {Nupam P.}",
note = "Funding Information: We thank John Cleveland for critical reading of the manuscript and various suggestions. N.P.M. is a recipient of NIH/NCI grant (5R01CA135328), Department of Defense (W81XWH-14-1-0002, W81XWH-14-1-0003, and W81XWH-15-1-0312), Bankhead-Coley (6BC08), and Miles-for-Moffitt Award (09-33661-15-13). K.M. is supported by Department of Defense awards (W81XWH-12-1-0248, W81XWH-14-1-0251, and W81XWH-15-1-0059). This work was supported in part by the Core Facilities at Moffitt Cancer Center and by Cancer Center Support Grant P30 CA076292. The Moffitt Cancer Center has filed patent applications as follows: ”Antibodies specific for phosphorylated histones and uses thereof” (US patent no. 9,594,084; serial no. 13700955.1; 14/124,662; 15/457,269), and “Inhibitors of ACK1/TNK2 Tyrosine Kinase” (patent application no. 14/910,486 and PCT/US2016/045096). K.M. and N.P.M. are named as inventors on a patent for antibodies specific for phosphorylated histones, and K.M., H.R.L., N.J.L., and N.P.M. are named as inventors on ACK1/TNK2 kinase inhibitors. Both the patents have been licensed by TechnoGenesys, Inc. K.M. and N.P.M. are co-founders of TechnoGenesys, Inc., own stock, and serve as consultants for TechnoGenesys, Inc. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = jun,
day = "12",
doi = "10.1016/j.ccell.2017.05.003",
language = "English",
volume = "31",
pages = "790--803.e8",
journal = "Cancer Cell",
issn = "1535-6108",
number = "6",
}