Tumor suppressor FBXO11 drives ubiquitin proteasomal degradation of KIF2C to limit ovarian cancer progression and is transcriptionally repressed by ZNF217.

Recent findings have indicated that the F-box E3 ubiquitin ligase, F-box only protein 11 (FBXO11), may serve a tumor-suppressing role in certain types of cancers. However, its specific function in ovarian cancer (OC) remains to be elucidated. This study revealed that FBXO11 expression is reduced in OC tissues compared to normal tissues. To assess the role of FBXO11 in OC cells, we established stable human OC cell lines with tetracycline-inducible (Tet-on) expression of FBXO11 CDS or shRNA. FBXO11 inhibited OC cell proliferation, colony formation, migration, invasion, and cell cycle transition from G0/G1 to S phase in vitro. Moreover, FBXO11 suppressed xenograft tumor growth in mice in vivo. Concurrently, FBXO11 reduced the volume of ascites and the number of metastatic tumor nodules in the peritoneal metastasis model. Mechanistically, FBXO11 promoted kinesin family member 2C (KIF2C) to undergo K48-linked ubiquitination and proteasomal degradation, and KIF2C knockdown reversed the tumor-promoting function of FBXO11 downregulation. Additionally, we demonstrated that FBXO11 is a transcriptional target of zinc-finger protein 217 (ZNF217), a known transcriptional repressor that has been implicated in the promotion of OC progression and the prediction of poor prognosis. In summary, FBXO11 functions as a tumor suppressor in OC through ubiquitin-proteasomal degradation of KIF2C; and the low expression level of FBXO11 in OC may be attributed to its transcriptional inhibition by transcription factor ZNF217. These findings provided new insights into understanding the molecular mechanism of OC progression.