Nature genetics, 2020-10, Vol.52 (10), p.1011-1017
2020
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- Autor(en) / Beteiligte
- Titel
- Chromatin binding of FOXA1 is promoted by LSD1-mediated demethylation in prostate cancer
- Ist Teil von
- Nature genetics, 2020-10, Vol.52 (10), p.1011-1017
- Ort / Verlag
- United States: Nature Publishing Group
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor , but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2) , but also acts as a steroid hormone receptor coactivator through mechanisms that are unclear. Here we show, in prostate cancer cells, that LSD1 associates with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding. Mechanistically, we demonstrate that LSD1 positively regulates FOXA1 binding by demethylating lysine 270, adjacent to the wing2 region of the FOXA1 DNA-binding domain. Acting through FOXA1, LSD1 inhibition broadly disrupted androgen-receptor binding and its transcriptional output, and dramatically decreased prostate cancer growth alone and in synergy with androgen-receptor antagonist treatment in vivo. These mechanistic insights suggest new therapeutic strategies in steroid-driven cancers.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1061-4036eISSN: 1546-1718DOI: 10.1038/s41588-020-0681-7Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7541538
- Format
- –
- Schlagworte
- Androgen Receptor Antagonists - pharmacology, Androgen receptors, Androgens, Animals, Binding, Binding sites, Cancer, Cell growth, Cell Line, Tumor, Chromatin, Chromatin - genetics, Demethylation, Deoxyribonucleic acid, DNA, DNA methylation, DNA Methylation - genetics, DNA-Binding Proteins - genetics, Estrogen, Estrogens, Gene expression, Gene Expression Regulation, Neoplastic - drug effects, Gene Knockout Techniques, Gonadal Steroid Hormones - genetics, Hepatocyte Nuclear Factor 3-alpha - genetics, Heterografts, Histone Demethylases - genetics, Histone H3, Histones, Humans, Ligands, Lysine, Male, Mice, Prevention, Prostate - metabolism, Prostate - pathology, Prostate cancer, Prostatic Neoplasms - genetics, Prostatic Neoplasms - pathology, Protein Binding - genetics, Protein expression, Proteins, Receptors, Receptors, Androgen - genetics, Recruitment, Steroid hormone receptor coactivator, Steroid hormone receptors, Steroids