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Celastrol recruits UBE3A to recognize and degrade the DNA binding domain of steroid receptors

Oncogene volume 41, pages 4754–4767 (2022)Cite this article

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Abstract

Strategies to degrade steroid receptors and their alternative splicing isoforms are critical for disease management. Here we report that celastrol recruited the ubiquitin ligase UBE3A and degraded androgen receptor (AR), AR-v7, and glucocorticoid receptor (GR) to suppress prostate cancer development. UBE3A was not an optimal endogenous AR ubiquitin ligase in mice and patients, but celastrol promoted the interaction between UBE3A and AR. Multiple domains of AR, including the DNA binding domain (DBD), were implicated into the UBE3A-AR interaction. Sharing a conserved DBD, GR, AR-v7, and other steroid receptors were recognized and degraded by UBE3A after celastrol treatment. Thus, celastrol suppressed prostate cancer cell proliferation more potently than enzalutamide. Modifying the carboxyl group of celastrol improved its anti-tumor activity. Together, our findings revealed that celastrol might be a potential molecular glue to enhance the interaction between UBE3A and steroid receptors to degrade multiple steroid receptors and splicing isoforms in prostate cancer, paving a way for further drug optimization and disease treatment.

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Fig. 1: UBE3A is involved in the celastrol-induced AR degradation.
Fig. 2: Celastrol recruits UBE3A as an AR ubiquitin ligase.
Fig. 3: Multiple domains of AR are involved in the celastrol induced degradation.
Fig. 4: Celastrol recruits UBE3A to degrade AR-v7.
Fig. 5: Celastrol recruits UBE3A to degrade steroid receptors.
Fig. 6: Celastrol recruits UBE3A to degrade GR.
Fig. 7: Essential moiety of celastrol for AR degradation.

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Data availability

The data used and/or analysed during this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the staff members (Zhuo Yang, et al) of the chemical biology core facility, the high-performance computing service platform, and the bioinformatics core in Shanghai Institute of Biochemistry and Cell Biology (SIBCB), mass spectrometry staff members of the National Facility for Protein in Shanghai (NFPS), and the Zhangjiang Lab and staff members (Pengyu Wang, et al.) of Bio-Med Big Data Center /Shanghai Institute of Nutrition and Health (SINH) for providing technical support and assistance in data collection and analysis. This work was supported by funding from the National Key R&D Program of China (2018YFA0508200 to ZL; 2019YFA0802103 and 2018YFA0508200 to RH), National Natural Science Foundation of China (92157101 to ZL; 81973166, 91753207 to BZ; 91853128, 81525019 to RH). RH was also supported by funding from Department of Science and Technology of Zhejiang Province (Proj. No. 2021C03104).

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Author notes

  1. These authors contributed equally: Qilong Tan, Ziqun Liu, Xiaobo Gao, Yibo Wang.

Authors and Affiliations

  1. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China

    Qilong Tan, Ziqun Liu, Jiahui Chen & Zhenfei Li

  2. Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China

    Xiaobo Gao

  3. State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China

    Xiaobo Gao & Ronggui Hu

  4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Yibo Wang, Liuchun Liang & Bing Zhou

  5. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China

    Yibo Wang & Bing Zhou

  6. Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China

    Xuefeng Qiu & Hongqian Guo

  7. Department of Urology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China

    Shengsong Huang & Denglong Wu

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Contributions

ZL initiated the project. ZL, RH and BZ designed the studies. QT, ZQL, XG and JC conducted functional assay. BZ, YW and LL synthesized celastrol related probes and compounds. XQ, HG, DW and SH were responsible for clinical data. All authors discussed the results and commented on the manuscript.

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Correspondence to Bing Zhou, Ronggui Hu or Zhenfei Li.

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Tan, Q., Liu, Z., Gao, X. et al. Celastrol recruits UBE3A to recognize and degrade the DNA binding domain of steroid receptors. Oncogene 41, 4754–4767 (2022). https://doi.org/10.1038/s41388-022-02467-8

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