A new study in Cancer Cell describes an epigenetic mechanism that increases androgen receptor (AR) transcription in castration-resistant prostate cancer (CRPC) via the nonreceptor tyrosine kinase ACK-1, WD repeat-containing protein 5 (WDR5), and histone-lysine N-methyltransferase 2D (KMT2D, also known as MLL2). An ACK-1-specific inhibitor suppressed both AR and AR-V7 levels and reduced in vivo CRPC tumour growth.

ACK-1 expression had previously been shown to correlate with prostate cancer progression to castration resistance and poor prognosis. Mahajan et al. investigated epigenetic mechanisms in CRPC pathogenesis and found phosphorylation of tyrosine 88 in histone H4 (pY88-H4) in three of five tested CRPC samples and predominantly in ACK-1-positive cells. Suppression of ACK-1 through knockdown or the inhibitor (R)-9bMS abrogated pY88-H4. pY88-H4 marks were found in distinct regions upstream of AR that seemed to act as enhancers of AR.

ACK-1 activity was required for AR expression in an androgen-deprived setting

Further studies in prostate cancer cell lines showed that ACK-1 activity was required for AR expression in an androgen-deprived setting. In addition, ACK-1 inhibition suppressed both AR and AR-V7 expression and had effects on DNA repair, transcription factor E2F, and MYC target gene signatures. Evaluation of the epigenetic mechanism revealed that a complex of WDR5–MLL2 recognizes pY88-H4 marks and creates transcriptionally activating H3K4me3 marks that promote AR transcription.

Analyses of clinical samples suggested that pY88-H4, H3K4me3, and AR expression increase during prostate cancer progression. In mouse xenograft models of CRPC, (R)-9bMS treatment halted tumour growth. The authors suggest that an epigenetic circuit of ACK1–pY88-H4–WDR5–MLL2–AR drives CRPC and is required to maintain the malignant state.