Fig. 9: FBXO32 drives cancer progression via stabilizing D-type cyclins.

Schematic illustration of the protein stability of cyclin D coordinated by FBXO32 and GSK-3β. In normal cells, cyclin D protein is phosphorylated by GSK-3β kinase at the Thr-288 and Thr-286 site, then recognized and added the K48-linked ubiquitin chains by other E3 ligases, which leads to the degradation of cyclin D in a proteasome-dependent manner. While in cancer cells, GSK-3β is phosphorylated and then inactivated, which contributes to the dephosphorylation of cyclin D. Highly expressed FBXO32 in tumor tissues recognizes dephosphorylated cyclin D and catalyzes the K27-linked polyubiquitination of cyclin D1 at the K58 site, suppressing the degradation of cyclin D1, which leads to uncontrolled cell cycle and cancer progression. Graphical abstract was created in BioRender (https://BioRender.com/h63r237).