Targeting KDM4A-AS1 represses AR/AR-Vs deubiquitination and enhances enzalutamide response in CRPC

Castration-resistant prostate cancer (CRPC) is a highly malignant type of advanced cancer resistant to androgen deprivation therapy. One of the important mechanisms for the development of CRPC is the persistent imbalanced regulation of AR and AR splice variants (AR/AR-Vs). In this study, we reported...

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Published inOncogene Vol. 41; no. 3; pp. 387 - 399
Main Authors Zhang, Boya, Zhang, Mingpeng, Yang, Yanjie, Li, Qi, Yu, Jianpeng, Zhu, Shimiao, Niu, Yuanjie, Shang, Zhiqun
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group UK 12.01.2022
Subjects
Aged
Animals
Benzamides - pharmacology
Benzamides - therapeutic use
Cell Line, Tumor
Humans
Jumonji Domain-Containing Histone Demethylases - metabolism
Male
Mice
Nitriles - pharmacology
Nitriles - therapeutic use
Phenylthiohydantoin - pharmacology
Phenylthiohydantoin - therapeutic use
Prostatic Neoplasms, Castration-Resistant - drug therapy
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Summary:Castration-resistant prostate cancer (CRPC) is a highly malignant type of advanced cancer resistant to androgen deprivation therapy. One of the important mechanisms for the development of CRPC is the persistent imbalanced regulation of AR and AR splice variants (AR/AR-Vs). In this study, we reported KDM4A-AS1, a recently discovered lncRNA, as a tumor promoter that was significantly increased in CRPC cell lines and cancer tissues. Depletion of KDM4A-AS1 significantly reduced cell viability, proliferation, migration in vitro, and tumor growth in vivo. We found that by binding to the NTD domain, KDM4A-AS1 enhances the stability of USP14-AR/AR-Vs complex, and promoted AR/AR-Vs deubiquitination to protect it from MDM2-mediated ubiquitin-proteasome degradation. Moreover, KDM4A-AS1 was found to enhance CRPC drug resistance to enzalutamide by repressing AR/AR-Vs degradation; antisense oligonucleotide drugs targeting KDM4A-AS1 significantly reduced the growth of tumors with enzalutamide resistance. Taken together, our results indicated that KDM4A-AS1 played an important role in the progression of CRPC and enzalutamide resistance by regulating AR/AR-Vs deubiquitination; targeting KDM4A-AS1 has broad clinical application potential.
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ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-021-02103-x