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

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

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87 Scopus citations

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.

Original language	English
Pages (from-to)	790-803.e8
Journal	Cancer Cell
Volume	31
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2017.05.003
State	Published - Jun 12 2017

Keywords

ACK1
AR
AR-V7
TNK2
castration resistance
enzalutamide
epigenetics
histone
prostate cancer
small-molecule inhibitor
tyrosine phosphorylation

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@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.}",

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doi = "10.1016/j.ccell.2017.05.003",

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T1 - ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer

AU - Mahajan, Kiran

AU - Malla, Pavani

AU - Lawrence, Harshani R.

AU - Chen, Zhihua

AU - Kumar-Sinha, Chandan

AU - Malik, Rohit

AU - Shukla, Sudhanshu

AU - Kim, Jongphil

AU - Coppola, Domenico

AU - Lawrence, Nicholas J.

AU - Mahajan, Nupam P.

PY - 2017/6/12

Y1 - 2017/6/12

N2 - 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.

AB - 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.

KW - ACK1

KW - AR

KW - AR-V7

KW - TNK2

KW - castration resistance

KW - enzalutamide

KW - epigenetics

KW - histone

KW - prostate cancer

KW - small-molecule inhibitor

KW - tyrosine phosphorylation

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U2 - 10.1016/j.ccell.2017.05.003

DO - 10.1016/j.ccell.2017.05.003

M3 - Article

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AN - SCOPUS:85020656802

SN - 1535-6108

VL - 31

SP - 790-803.e8

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

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

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