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Updated: Feb 28, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

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

Kiran Mahajan1, Pavani Malla2, Harshani R Lawrence3

  • 1Tumor Biology Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.

Cancer Cell
|June 14, 2017
PubMed

Insights

A novel epigenetic circuit involving tyrosine kinase ACK1 drives castration-resistant prostate cancer (CRPC) by promoting androgen receptor (AR) expression. Inhibiting ACK1 reduces AR and AR-V7 levels, offering a potential therapeutic strategy for CRPC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Androgen receptor (AR) signaling is crucial for prostate cancer progression.
  • Castration-resistant prostate cancer (CRPC) remains a significant clinical challenge, with AR antagonists often failing.
  • The AR splice variant AR-V7 contributes to therapeutic resistance.

Purpose of the Study:

  • To elucidate the epigenetic mechanisms driving AR expression in CRPC.
  • To identify novel therapeutic targets for overcoming resistance to AR antagonists.

Main Methods:

  • Investigated the role of tyrosine kinase ACK1 (TNK2) in regulating AR transcription.
  • Utilized epigenetic analysis to identify histone modifications upstream of the AR gene.
  • Employed an ACK1 inhibitor ((R)-9bMS) to assess its impact on AR signaling and CRPC cell growth.

Main Results:

  • ACK1 phosphorylates histone H4 at tyrosine 88 (H4-Y88) upstream of the AR transcription start site.
  • The WDR5/MLL2 complex recognizes H4-Y88 phosphorylation, leading to H3K4 trimethylation and enhanced AR transcription.
  • Inhibition of ACK1 reversed H4-Y88 epigenetic marks, reduced AR and AR-V7 levels, and sensitized CRPC cells to therapy.
  • Targeting this epigenetic circuit mitigated CRPC tumor growth.

Conclusions:

  • A feedforward epigenetic circuit, ACK1/pY88-H4/WDR5/MLL2/AR, drives CRPC.
  • This circuit is essential for maintaining the malignant state in CRPC.
  • ACK1 inhibition represents a promising therapeutic strategy for CRPC by targeting this critical epigenetic regulatory pathway.
Keywords:
ACK1ARAR-V7TNK2castration resistanceenzalutamideepigeneticshistoneprostate cancersmall-molecule inhibitortyrosine phosphorylation

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