Suppression of the USP10/CCND1 axis induces glioblastoma cell apoptosis

Tong Sun1,2, Yu-jia Xu1,3, Shuo-yi Jiang1, Zhuan Xu1, Bi-yin Cao2, Gautam Sethi4, Yuan-ying Zeng5, Yan Kong2, Xin-liang Mao1,3,6
1 Department of Pharmacology, Soochow University, Suzhou 215123, China
2 Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou 215100, China
3 Guangdong Key Laboratory of Protein Modifications and Degradation, School of Basic Medicine, Guangzhou Medical University, Guangzhou 511436, China
4 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
5 Department of Oncology, Suzhou Municipal Hospital, Suzhou 215100, China
6 Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
Correspondence to: Yuan-ying Zeng:, Yan Kong:, Xin-liang Mao:,
DOI: 10.1038/s41401-020-00551-x
Received: 6 July 2020
Accepted: 29 September 2020
Advance online: 12 November 2020


Recent studies show that the expression of CCND1, a key factor in cell cycle control, is increased following the progress and deteriotation of glioma and predicts poor outcomes. On the other hand, dysregulated deubiquitinase USP10 also predicts poor prognosis for patients with glioblastoma (GBM). In the present study, we investigated the interplay between CCND1 protein and USP10 in GBM cells. We showed that the expression of CCND1 was significantly higher in both GBM tissues and GBM-derived stem cells. USP10 interacted with CCND1 and prevented its K48- but not K63-linked polyubiquitination in GBM U251 and HS683 cells, which led to increased CCND1 stability. Consistent with the action of USP10 on CCND1, knockdown of USP10 by single-guided RNA downregulated CCND1 and caused GBM cell cycle arrest at the G1 phase and induced GBM cell apoptosis. To implement this finding in the treatment of GBMs, we screened a natural product library and found that acevaltrate (AVT), an active component derived from the herbal plant Valeriana jatamansi Jones was strikingly potent to induce GBM cell apoptosis, which was confirmed by the Annexin V staining and activation of the apoptotic signals. Furthermore, we revealed that AVT concentration-dependently suppressed USP10-mediated deubiquitination on CCND1 therefore inducing CCND1 protein degradation. Collectively, the present study demonstrates that the USP10/CCND1 axis could be a promising therapeutic target for patients with GBMs.
Keywords: glioblastoma; USP10; cyclin D1; acevaltrate; apoptosis

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