2. Academic Validation
  3. Suppression of the USP10/CCND1 axis induces glioblastoma cell apoptosis

Suppression of the USP10/CCND1 axis induces glioblastoma cell apoptosis

  • Acta Pharmacol Sin. 2021 Aug;42(8):1338-1346. doi: 10.1038/s41401-020-00551-x.
Tong Sun  # 1 2,  Yu-Jia Xu  # 1 3,  Shuo-Yi Jiang 1,  Zhuan Xu 1,  Bi-Yin Cao 2,  Gautam Sethi 4,  Yuan-Ying Zeng 5,  Yan Kong 6,  Xin-Liang Mao 7 8 9
Affiliations

Affiliations

  • 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. zengyuanying@163.com.
  • 6 Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou, 215100, China. kong0919@163.com.
  • 7 Department of Pharmacology, Soochow University, Suzhou, 215123, China. xinliangmao@gzhmu.edu.cn.
  • 8 Guangdong Key Laboratory of Protein Modifications and Degradation, School of Basic Medicine, Guangzhou Medical University, Guangzhou, 511436, China. xinliangmao@gzhmu.edu.cn.
  • 9 Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. xinliangmao@gzhmu.edu.cn.
  • # Contributed equally.
PMID: 33184448 DOI: 10.1038/s41401-020-00551-x
Abstract

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

USP10; acevaltrate; apoptosis; cyclin D1; glioblastoma.

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