Targeting theKDM4B-AR-c-Mycaxis promotes sensitivity to androgen receptor-targeted therapy in advanced prostate cancer

Tang, Dong-E1; Dai, Yong1; He, Jia-Xi2; Lin, Lie-Wen1; Leng, Qi-Xin2; Geng, Xin-Yan3; Fu, De-Xue4; Jiang, Hao-Wu5,6; Xu, Song-Hui1,2

2020-08-28

10.1002/path.5495

JOURNAL OF PATHOLOGY   影响因子和分区

0022-3417

1096-9896

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. (c) 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

KDM4B prostate cancer c-Myc enzalutamide resistance androgen receptor histone demethylase castration-resistant prostate cancer

SCI

英语

第一 ; 通讯

National Natural Science Foundation of China[31700795] ; Natural Science Foundation of Guangdong Province of China[2017A030310629]

Oncology ; Pathology

Oncology ; Pathology

WOS:000563272300001

WILEY

CLINICAL MEDICINE

Web of Science

1.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp, Dept Clin Med Res Ctr,Affiliated Hosp 1,Clin Med, Shenzhen, Peoples R China
2.Univ Maryland, Sch Med, Dept Pathol, Marlene & Stewart Greenebaum Canc Ctr, 22 S Greene St, Baltimore, MD 21201 USA
3.Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Dept Biochem, Baltimore, MD 21201 USA
4.Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Dept Surg, Sch Med, Baltimore, MD 21201 USA
5.Washington Univ, Sch Med, Dept Anesthesiol, St Louis, MO 63110 USA
6.Washington Univ, Sch Med, Ctr Study Itch, St Louis, MO USA

Tang, Dong-E,Dai, Yong,He, Jia-Xi,et al. Targeting theKDM4B-AR-c-Mycaxis promotes sensitivity to androgen receptor-targeted therapy in advanced prostate cancer[J]. JOURNAL OF PATHOLOGY,2020,252(2):101-113.

Tang, Dong-E.,Dai, Yong.,He, Jia-Xi.,Lin, Lie-Wen.,Leng, Qi-Xin.,...&Xu, Song-Hui.(2020).Targeting theKDM4B-AR-c-Mycaxis promotes sensitivity to androgen receptor-targeted therapy in advanced prostate cancer.JOURNAL OF PATHOLOGY,252(2),101-113.

Tang, Dong-E,et al."Targeting theKDM4B-AR-c-Mycaxis promotes sensitivity to androgen receptor-targeted therapy in advanced prostate cancer".JOURNAL OF PATHOLOGY 252.2(2020):101-113.