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

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 e...

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Published in:Cancer gene therapy 2022-05, Vol.29 (5), p.543-557
Main Authors: Tang, Donge, He, Jiaxi, Dai, Yong, Geng, Xinyan, Leng, Qixin, Jiang, Haowu, Sun, Rui, Xu, Songhui
Format: Article
Language:English
Subjects:
Benzamides - therapeutic use
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm - genetics
Histone Deacetylases - genetics
Humans
Male
MicroRNAs - genetics
Mucoproteins - genetics
Nitriles - therapeutic use
Oncogene Proteins - genetics
Phenylthiohydantoin - therapeutic use
Prostatic Neoplasms, Castration-Resistant - drug therapy
Prostatic Neoplasms, Castration-Resistant - genetics
Prostatic Neoplasms, Castration-Resistant - pathology
Receptors, Androgen - genetics
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Summary: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.
ISSN:1476-5500
DOI:10.1038/s41417-021-00332-6