Chromatin binding of FOXA1 is promoted by LSD1-mediated demethylation in prostate cancer
| Autor: | Changmeng Cai, Susan Patalano, My Phu Luong, Yi Liang, Steven P. Balk, Muqing Li, Wanting Han, Anna Besschetnova, Housheng Hansen He, Jude Owiredu, Dong Han, Eva Corey, David Barrett, Zifeng Wang, Mingyu Liu, Jessica Petricca, Musaddeque Ahmed, Shuai Gao, Feng Zhou, Sen Chen, Jill A. Macoska, Sujun Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Hepatocyte Nuclear Factor 3-alpha
Male animal structures Steroid hormone receptor medicine.medical_treatment Biology Article Gene Knockout Techniques Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Coactivator Androgen Receptor Antagonists Genetics medicine Animals Humans Gonadal Steroid Hormones Transcription factor 030304 developmental biology Histone Demethylases 0303 health sciences Chromatin binding Prostate Prostatic Neoplasms DNA Methylation Chromatin Cell biology Demethylation DNA-Binding Proteins Gene Expression Regulation Neoplastic Androgen receptor Steroid hormone Receptors Androgen Heterografts FOXA1 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Nature genetics |
| ISSN: | 1546-1718 1061-4036 |
| Popis: | FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor1-4, 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)5,6, 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink