2. Academic Validation
  3. Inhibition of USP10 induces myeloma cell apoptosis by promoting cyclin D3 degradation

Inhibition of USP10 induces myeloma cell apoptosis by promoting cyclin D3 degradation

  • Acta Pharmacol Sin. 2023 Apr 13. doi: 10.1038/s41401-023-01083-w.
Yu-Jia Xu # 1 2,  Kun Zeng # 3,  Ying Ren 3,  Chen-Yu Mao 4,  Ying-Hui Ye 1,  Xiao-Ting Zhu 1 5,  Zi-Ying Sun 2,  Bi-Yin Cao 3,  Zu-Bin Zhang 3,  Guo-Qiang Xu 3,  Zhen-Qian Huang 6,  Xin-Liang Mao 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Hematology, the First Affiliated Hospital & GMU-GIBH Joint School of Life Sciences, the Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, 510120, China.
  • 2 Guangdong & Guangzhou Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
  • 3 Department of Pharmacology, Soochow University, Suzhou, 215123, China.
  • 4 School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China.
  • 5 Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
  • 6 Department of Hematology, the First Affiliated Hospital & GMU-GIBH Joint School of Life Sciences, the Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, 510120, China. huangzq2013@163.com.
  • 7 Department of Hematology, the First Affiliated Hospital & GMU-GIBH Joint School of Life Sciences, the Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, 510120, China. xinliangmao@gzhmu.edu.cn.
  • 8 Guangdong & Guangzhou Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China. xinliangmao@gzhmu.edu.cn.
  • 9 Department of Pharmacology, Soochow University, Suzhou, 215123, China. xinliangmao@gzhmu.edu.cn.
  • 10 Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. xinliangmao@gzhmu.edu.cn.
  • # Contributed equally.
PMID: 37055530 DOI: 10.1038/s41401-023-01083-w
Abstract

The cell cycle regulator cyclin D3 (CCND3) is highly expressed in multiple myeloma (MM) and it promotes MM cell proliferation. After a certain phase of cell cycle, CCND3 is rapidly degraded, which is essential for the strict control of MM cell cycle progress and proliferation. In the present study, we investigated the molecular mechanisms regulating CCND3 degradation in MM cells. By utilizing affinity purification-coupled tandem mass spectrometry, we identified the Deubiquitinase USP10 interacting with CCND3 in human MM OPM2 and KMS11 cell lines. Furthermore, USP10 specifically prevented CCND3 from K48-linked polyubiquitination and proteasomal degradation, therefore enhancing its activity. We demonstrated that the N-terminal domain (aa. 1-205) of USP10 was dispensable for binding to and deubiquitinating CCND3. Although Thr283 was important for CCND3 activity, it was dispensable for CCND3 ubiquitination and stability modulated by USP10. By stabilizing CCND3, USP10 activated the CCND3/CDK4/6 signaling pathway, phosphorylated Rb, and upregulated CDK4, CDK6 and E2F-1 in OPM2 and KMS11 cells. Consistent with these findings, inhibition of USP10 by Spautin-1 resulted in accumulation of CCND3 with K48-linked polyubiquitination and degradation that synergized with Palbociclib, a CDK4/6 inhibitor, to induce MM cell Apoptosis. In nude mice bearing myeloma xenografts with OPM2 and KMS11 cells, combined administration of Spautin-l and Palbociclib almost suppressed tumor growth within 30 days. This study thus identifies USP10 as the first Deubiquitinase of CCND3 and also finds that targeting the USP10/CCND3/CDK4/6 axis may be a novel modality for the treatment of myeloma.

Keywords

cyclin D3; cyclin-dependent kinase; mass spectrometry; multiple myeloma; ubiquitin specific peptidase 10.

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