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
  • 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. [email protected].
  • 8. Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China. [email protected].
  • 9. Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China. [email protected].
  • 10. Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China. [email protected].
  • # 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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