# Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $338,664

## Abstract

Abstract
For over half a century, prostate cancer research has focused on the Androgen receptor (AR),
its role in the initiation of the disease and progression to the highly metastatic stage, castration
resistant prostate cancer (CRPC). While AR antagonists such as enzalutamide or androgen-
synthesis inhibitor abiraterone dampen AR functional activity, these are often ineffective long
term, as the recalcitrant disease recurs within 2-3 years. CRPCs not only thrive under low or
castrate levels of androgen, but also fastidiously maintain functional AR. Consequently, anti-
androgen-resistance has become one of the most vexing problems in prostate cancer therapy.
Despite intensive efforts, targeting co-factors that regulate AR and its splice variant, AR-V7
transcription, directly and efficaciously, with small molecule inhibitors has not yet been
achieved. We uncovered that AR recruits the oncogene ACK1, a non-receptor tyrosine kinase,
to regulate its own expression- setting up a pathological positive feedback loop in androgen
deprived condition. Mechanistically, activated ACK1 modifies chromatin via phosphorylation of
the histone H4 at a novel site, tyrosine 88 (pY88-H4), upstream of the AR gene at three sites
AREM1-3, to promote transcription. Conversely, reversal of this pY88-H4 histone modification
by treatment with a novel ACK1 inhibitor, (R)-9bMS, or overexpression of the H4Y88F mutant
significantly suppressed transcription of the full length AR as well as AR-V7 splice variant,
consequently downregulating expression of AR-target genes, such as PSA. Moreover, we
demonstrate that WDR5/MLL2 histone-Lysine N-Methyltransferase complex, interact with the
pY88-H4 epigenetic marks, deposit the transcriptionally activating H3K4 tri-methyl marks in
trans, thus uncovering a novel mode of epigenetic regulation at the AR locus. Based on these
extensive preliminary data, we hypothesize that inhibition of ACK1 epigenetic regulator activity
that suppresses AR transcription and block production of AR splice variants will be critical to
combat enzalutamide- and abiraterone-resistant CRPCs. To address this hypothesis, we will
pursue the following aims:
Aim 1. Assess the functional role of pY88-H4 deposition sites AREM1-3 on AR/AR-V7
transcription in CRPCs.
Aim 2. Examine genome wide MLL2/WDR5/ASH2L and pY88-H4 co-association and its role in
driving AR/AR-V7 expression and CRPC progression.
Aim 3. Detail characterization of ACK1 inhibitor (R)-9bMS to overcome enzalutamide &
abiraterone-resistance and ADME/DMPK studies.

## Key facts

- **NIH application ID:** 10112834
- **Project number:** 5R01CA208258-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Nupam P Mahajan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $338,664
- **Award type:** 5
- **Project period:** 2017-03-20 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112834

## Citation

> US National Institutes of Health, RePORTER application 10112834, Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer (5R01CA208258-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112834. Licensed CC0.

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