Targeting KDM1B-dependent miR-215-AR-AGR2-axis promotes sensitivity to enzalutamide-resistant prostate cancer

Donge Tang; Jiaxi He; Yong Dai; Xinyan Geng; Qixin Leng; Haowu Jiang; Rui Sun; Songhui Xu

doi:10.1038/s41417-021-00332-6

Targeting KDM1B-dependent miR-215-AR-AGR2-axis promotes sensitivity to enzalutamide-resistant prostate cancer

Donge Tang, Jiaxi He, Yong Dai, Xinyan Geng, Qixin Leng, Haowu Jiang, Rui Sun, Songhui Xu

Department of Anesthesiology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Post-translational modifications of histones by histone demethylases plays an important role in the regulation of gene transcription and are implicated in cancers. Castrate resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. However, the role of KDM1B involved in next generation anti-enzalutamide resistance and the mechanisms of KDM1B regulation are poorly defined. Here, we show that KDM1B is upregulated and correlated with prostate cancer progression and poor prognosis. Downregulation of miR-215 is correlated with overexpression of KDM1B in enzalutamide-resistant prostate cancer cells, which promotes AR-dependent AGR2 transcription and regulates the sensitivity to next generation AR-targeted therapy. Inhibition of KDM1B significantly inhibits prostate tumor growth and improves enzalutamide treatments through AGR2 suppression. Our studies demonstrate inhibition of KDM1B can offer a viable therapeutic option to overcome enzalutamide resistance in tumors with deregulated miR-215-KDM1B-AR-AGR2 signaling axis.

Original language	English
Pages (from-to)	543-557
Number of pages	15
Journal	Cancer gene therapy
Volume	29
Issue number	5
DOIs	https://doi.org/10.1038/s41417-021-00332-6
State	Published - May 2022

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title = "Targeting KDM1B-dependent miR-215-AR-AGR2-axis promotes sensitivity to enzalutamide-resistant prostate cancer",

abstract = "Post-translational modifications of histones by histone demethylases plays an important role in the regulation of gene transcription and are implicated in cancers. Castrate resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. However, the role of KDM1B involved in next generation anti-enzalutamide resistance and the mechanisms of KDM1B regulation are poorly defined. Here, we show that KDM1B is upregulated and correlated with prostate cancer progression and poor prognosis. Downregulation of miR-215 is correlated with overexpression of KDM1B in enzalutamide-resistant prostate cancer cells, which promotes AR-dependent AGR2 transcription and regulates the sensitivity to next generation AR-targeted therapy. Inhibition of KDM1B significantly inhibits prostate tumor growth and improves enzalutamide treatments through AGR2 suppression. Our studies demonstrate inhibition of KDM1B can offer a viable therapeutic option to overcome enzalutamide resistance in tumors with deregulated miR-215-KDM1B-AR-AGR2 signaling axis.",

author = "Donge Tang and Jiaxi He and Yong Dai and Xinyan Geng and Qixin Leng and Haowu Jiang and Rui Sun and Songhui Xu",

note = "Funding Information: We thank professor Mixson James (University of Maryland School of Medicine, USA) to give us a language editing and members of Cui and He laboratories for discussion and comments on the paper. Funding Information: Funding Support by the National Natural Science Foundation of China (No. 81370804), the Guangdong Provincial Science and Technology Plan Project (No. 2017B030314108), and the High-level Hospital Construction Project of Guangdong Provincial People{\textquoteright}s Hospital (KJ012021011) is gratefully acknowledged. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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AU - Tang, Donge

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AU - Dai, Yong

AU - Geng, Xinyan

AU - Leng, Qixin

AU - Jiang, Haowu

AU - Sun, Rui

AU - Xu, Songhui

N1 - Funding Information: We thank professor Mixson James (University of Maryland School of Medicine, USA) to give us a language editing and members of Cui and He laboratories for discussion and comments on the paper. Funding Information: Funding Support by the National Natural Science Foundation of China (No. 81370804), the Guangdong Provincial Science and Technology Plan Project (No. 2017B030314108), and the High-level Hospital Construction Project of Guangdong Provincial People’s Hospital (KJ012021011) is gratefully acknowledged. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022/5

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N2 - Post-translational modifications of histones by histone demethylases plays an important role in the regulation of gene transcription and are implicated in cancers. Castrate resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. However, the role of KDM1B involved in next generation anti-enzalutamide resistance and the mechanisms of KDM1B regulation are poorly defined. Here, we show that KDM1B is upregulated and correlated with prostate cancer progression and poor prognosis. Downregulation of miR-215 is correlated with overexpression of KDM1B in enzalutamide-resistant prostate cancer cells, which promotes AR-dependent AGR2 transcription and regulates the sensitivity to next generation AR-targeted therapy. Inhibition of KDM1B significantly inhibits prostate tumor growth and improves enzalutamide treatments through AGR2 suppression. Our studies demonstrate inhibition of KDM1B can offer a viable therapeutic option to overcome enzalutamide resistance in tumors with deregulated miR-215-KDM1B-AR-AGR2 signaling axis.

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Targeting KDM1B-dependent miR-215-AR-AGR2-axis promotes sensitivity to enzalutamide-resistant prostate cancer

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