2. Academic Validation
  3. Celastrol recruits UBE3A to recognize and degrade the DNA binding domain of steroid receptors

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

  • Oncogene. 2022 Sep 16. doi: 10.1038/s41388-022-02467-8.
Qilong Tan  # 1,  Ziqun Liu  # 1,  Xiaobo Gao  # 2 3,  Yibo Wang  # 4 5,  Xuefeng Qiu 6,  Jiahui Chen 1,  Liuchun Liang 4,  Hongqian Guo 6,  Shengsong Huang 7,  Denglong Wu 7,  Bing Zhou 8 9,  Ronggui Hu 10,  Zhenfei Li 11
Affiliations

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.
  • 2 Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China.
  • 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.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 5 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 6 Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China.
  • 7 Department of Urology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China.
  • 8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. zhoubing@simm.ac.cn.
  • 9 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. zhoubing@simm.ac.cn.
  • 10 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. coryhu@sibcb.ac.cn.
  • 11 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. zhenfei.li@sibcb.ac.cn.
  • # Contributed equally.
PMID: 36109631 DOI: 10.1038/s41388-022-02467-8
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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