| Autor: |
Tang, Dong‐E, Dai, Yong, He, Jia‐Xi, Lin, Lie‐Wen, Leng, Qi‐Xin, Geng, Xin‐Yan, Fu, De‐Xue, Jiang, Hao‐Wu, Xu, Song‐Hui |
| Předmět: |
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| Zdroj: |
Journal of Pathology; Oct2020, Vol. 252 Issue 2, p101-113, 13p |
| Abstrakt: |
The histone demethylase KDM4B functions as a key co‐activator for the androgen receptor (AR) and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 methylation marks. Constitutively active androgen receptor confers anti‐androgen resistance in advanced prostate cancer. However, the role of KDM4B in resistance to next‐generation anti‐androgens and the mechanisms of KDM4B regulation are poorly defined. Here we found that KDM4B is overexpressed in enzalutamide‐resistant prostate cancer cells. Overexpression of KDM4B promoted recruitment of AR to the c‐Myc (MYC) gene enhancer and induced H3K9 demethylation, increasing AR‐dependent transcription of c‐Myc mRNA, which regulates the sensitivity to next‐generation AR‐targeted therapy. Inhibition of KDM4B significantly inhibited prostate tumor cell growth in xenografts, and improved enzalutamide treatments through suppression of c‐Myc. Clinically, KDM4B expression was found upregulated and to correlate with prostate cancer progression and poor prognosis. Our results revealed a novel mechanism of anti‐androgen resistance via histone demethylase alteration which could be targeted through inhibition of KDM4B to reduce AR‐dependent c‐Myc expression and overcome resistance to AR‐targeted therapies. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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