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

Feng Li, Hongqiang Yu, Yujun Zhang, Yuanhang Ma, Xinlei Chen, Jie Zhang, Liangbo Sun, Rui Guo, Ying Wu, Ping Zheng, Xiaojun Wang, Ping Bie, Fengtian He (), Leida Zhang (), Chuanming Xie () and Haojun Xiong ()
Additional contact information
Feng Li: Army Medical University
Hongqiang Yu: Army Medical University
Yujun Zhang: Army Medical University
Yuanhang Ma: Army Medical University
Xinlei Chen: Army Medical University
Jie Zhang: Army Medical University
Liangbo Sun: Army Medical University
Rui Guo: Army Medical University
Ying Wu: Army Medical University
Ping Zheng: Army Medical University
Xiaojun Wang: Army Medical University
Ping Bie: The Third Affiliated Hospital of Chongqing Medical University
Fengtian He: Army Medical University
Leida Zhang: Army Medical University
Chuanming Xie: Army Medical University
Haojun Xiong: Army Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59407-9

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