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

D-type cyclins are key proteins that regulate the transition from the G1 to the S phase of the cell cycle. Consequently, abnormal levels of cyclin D are frequently observed in proliferative diseases such as cancer. However, the precise mechanisms that control the degradation of cyclin D proteins are not fully understood.

In this study, we identified F-box protein 32, also known as atrogin-1, as an E3 ubiquitin ligase that targets all three D-type cyclins for ubiquitination and subsequent stabilization. Specifically, we found that FBXO32 catalyzes the formation of lysine 27-linked polyubiquitin chains on cyclin D1 at the lysine 58 residue, leading to its stabilization.

Moreover, the dephosphorylation of cyclin D1, which occurs when glycogen synthase kinase-3 beta is inactive, facilitates the interaction between cyclin D1 and FBXO32, thereby promoting its ubiquitination. Furthermore, our experiments in mouse models demonstrated that FBXO32 promotes tumor growth, and increased levels of FBXO32 in cancer patients are associated with a poorer prognosis.

Additionally, disrupting the interaction between FBXO32 and cyclin D enhances the effectiveness of palbociclib, a drug that inhibits cyclin-dependent kinases 4 and 6, in killing tumor cells. Taken together, THZ531 these findings reveal that FBXO32 enhances the stability of cyclin D proteins through lysine 27-linked ubiquitination, contributing to cancer progression and potentially limiting the response of cancer cells to CDK4/6 inhibitors.