ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer

Kiran Mahajan; Pavani Malla; Harshani R Lawrence; Zhihua Chen; Chandan Kumar-Sinha; Rohit Malik; Sudhanshu Shukla; Jongphil Kim; Domenico Coppola; Nicholas J Lawrence; Nupam P Mahajan

doi:10.1016/j.ccell.2017.05.003

ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer

Cancer Cell. 2017 Jun 12;31(6):790-803.e8. doi: 10.1016/j.ccell.2017.05.003.

Authors

Affiliations

¹ Tumor Biology Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.
² Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
³ Chemical Biology Core, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.
⁴ Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
⁵ Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁶ Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.
⁷ Department of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
⁸ Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.
⁹ Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA. Electronic address: nupam.mahajan@moffitt.org.

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.

MeSH terms

Benzamides
Cell Proliferation / drug effects
Drug Resistance, Neoplasm
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic*
Histones / metabolism*
Humans
Male
Nitriles
Phenylthiohydantoin / analogs & derivatives
Phenylthiohydantoin / therapeutic use
Phosphorylation
Prostatic Neoplasms, Castration-Resistant / genetics*
Protein Kinase Inhibitors / pharmacology
Protein-Tyrosine Kinases / antagonists & inhibitors
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / physiology*
RNA, Messenger / metabolism
Receptors, Androgen / genetics*
Receptors, Androgen / metabolism
Tumor Cells, Cultured

Substances

Benzamides
Histones
Nitriles
Protein Kinase Inhibitors
RNA, Messenger
Receptors, Androgen
Phenylthiohydantoin
enzalutamide
Protein-Tyrosine Kinases
TNK2 protein, human

Abstract

MeSH terms

Substances

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