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• W2091097776 abstract "<h3>ABSTRACT</h3> Chromatin elements and regulators play important roles during progression of prostate cancer, however, their involvement in response to therapy is less well understood. Using comprehensive chromatin profiling of patient-derived tumors, we find that enhancer elements marked by H3K4me1 are highly enriched in aggressive therapy-resistant prostate cancers on important resistance-driving genes, such as those involved in FOXA1, NOTCH and TGF-β signaling. Importantly, by targeting H3K4me1-elements through inhibition of the MLL complex, a H3K4 methyltransferase, we reduced the proliferative capacity and H3K4me1-associated loci in enzalutamide-resistant prostate cancer lines. We identify AR, FOXA1, HOXB13 and SOX4 as a subset of core TFs that are critical for establishing transcriptional networks via active enhancer reprogramming during acquisition of resistance to therapy. Knock-down of SOX4 reduced cell proliferation and disrupted the H3K4me1 enhancer landscape, further suggesting a role for this TF in therapy-resistance. Overall, our data implicate H3K4me1-marked enhancers as a key epigenetic feature of therapy-resistance, implicate SOX4 in enhancer reprogramming and suggest use of MLL/MENIN inhibitors as a potential therapeutic strategy in high-grade and locally advanced prostate cancers that do not respond to traditional therapies." @default.
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• W2091097776 date "1991-06-15" @default.
• W2091097776 modified "2023-09-23" @default.
• W2091097776 title "Cerebrovascular events after myocardial infarction: analysis of the GISSI trial. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI)." @default.
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• W2091097776 doi "https://doi.org/10.1136/bmj.302.6790.1428" @default.
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