Epigenetic Reprogramming of Androgen Receptor by Histone H4 Tyr88-phosphorylation Promotes Castration Resistance
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ABSTRACT: Androgen receptor (AR) is critical for the progression of prostate cancer to the castration resistant (CRPC) state. Despite initial response, AR antagonists are ineffective long term in stifling AR activity due to their inability to repress expression of the AR or its splice variant, AR-V7. Here, we report that ACK1 tyrosine kinase, frequently deregulated in CRPCs, phosphorylates histone H4 at tyrosine 88, upstream of the AR transcription start site. WDR5/MLL2 complex reads the H4Y88 marks and modifies H3 in trans to deposit the transcriptionally activating H3K4 trimethyl marks, promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by ACK1 small molecule inhibitor, (R)-9bMS, sensitized naïve and enzalutamide-resistant cancer cells, repressed AR and AR-V7 levels to mitigate in vivo CRPC tumor growth. Thus, a feed-forward ACK1-H4-WDR5/MLL2-AR/AR-V7 epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state.
ORGANISM(S): Homo sapiens
PROVIDER: GSE79689 | GEO | 2017/03/01
SECONDARY ACCESSION(S): PRJNA316711
REPOSITORIES: GEO
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