2. Academic Validation
  3. F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression

F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression

  • Nat Commun. 2025 Apr 30;16(1):4060. doi: 10.1038/s41467-025-59407-9.
Feng Li # 1 2 3,  Hongqiang Yu # 1,  Yujun Zhang # 1,  Yuanhang Ma 4,  Xinlei Chen 1 5,  Jie Zhang 1,  Liangbo Sun 6,  Rui Guo 1,  Ying Wu 1,  Ping Zheng 1,  Xiaojun Wang 1,  Ping Bie 3,  Fengtian He 7,  Leida Zhang 8,  Chuanming Xie 9,  Haojun Xiong 10
Affiliations

Affiliations

  • 1 Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China.
  • 2 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China.
  • 5 Department of Clinical Laboratory, Army 958 Hospital of The Chinese People's Liberation Army, Chongqing, China.
  • 6 Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing, China.
  • 7 Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, China. hefengtian@tmmu.edu.cn.
  • 8 Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China. zhangleida@tmmu.edu.cn.
  • 9 Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China. chuanming506@126.com.
  • 10 Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China. xionghaojun@tmmu.edu.cn.
  • # Contributed equally.
PMID: 40307251 DOI: 10.1038/s41467-025-59407-9
Abstract

D-type cyclins (hereafter, cyclin D) are central regulators orchestrating G1/S cell cycle transition. Accordingly, aberrant expression of cyclin D is strongly correlated with proliferation-related diseases such as Cancer. However, the mechanisms regulating cyclin D turnover are incompletely elucidated. Here we identify FBXO32, namely atrogin-1, as the E3 ubiquitin Ligase that targets all three cyclin D for ubiquitination and stabilization. Specifically, FBXO32 catalyzes the lysine (Lys/K)27-linked polyubiquitination of cyclin D1 at the K58 site and subsequent stabilization. Moreover, GSK-3β inactivation-mediated dephosphorylation of cyclin D1 facilitates its interaction with FBXO32 and subsequent ubiquitination. Furthermore, FBXO32 exhibits tumor-promoting effect in mouse models and increased FBXO32 is associated with poor prognosis of Cancer patients. Additionally, disrupting the FBXO32-cyclin D axis enhances the tumor-killing effect of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib. Collectively, these findings reveal that FBXO32 enhances the protein stability of cyclin D via K27-linked ubiquitination, and contributes to Cancer progression and the limited response of Cancer cells to CDK4/6 inhibitors.

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