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

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.

• Authors: Qilong Tan, Ziqun Liu, Xiaobo Gao, Yibo Wang, Xuefeng Qiu, Jiahui Chen, Liuchun Liang, Hongqian Guo, Shengsong Huang, Denglong Wu, Bing Zhou, Ronggui Hu, Zhenfei Li
• Journal: Oncogene (Oncogene) Vol. 41 Issue 42 Pg. 4754-4767 (10 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 36109631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Pentacyclic Triterpenes
• Protein Isoforms
• Receptors, Androgen
• Receptors, Glucocorticoid
• Ubiquitins
• DNA
• UBE3A protein, human
• Ube3a protein, mouse
• Ubiquitin-Protein Ligases
• Ligases
• celastrol

Topics

• Animals
• DNA (metabolism)
• Humans
• Ligases
• Male
• Mice
• Pentacyclic Triterpenes
• Prostatic Neoplasms (drug therapy, genetics, pathology)
• Prostatic Neoplasms, Castration-Resistant (pathology)
• Protein Isoforms (chemistry, genetics)
• Receptors, Androgen (metabolism)
• Receptors, Glucocorticoid
• Ubiquitin-Protein Ligases (genetics)
• Ubiquitins