Hypomethylation-Enhanced F-Box Protein 32 Promotes Hepatocellular Carcinogenesis via Ubiquitin-Mediated PHLPP2 Degradation

F-Box Protein 32 (FBXO32), a F-box protein family member, exhibits oncogenic and tumor-suppressive roles in various carcinomas. However, its function and underlying molecular mechanisms in hepatocellular carcinoma (HCC) are still unknown. We observed that FBXO32 was overexpressed in HCC tissues than normal tissues, which is pertaining to poor prognosis in HCC patients. Functional tests demonstrated that FBXO32 enhanced HCC cell proliferation, invasion, and metastasis, which was confirmed in vivo using mouse models. Proteomics-based approaches and computational analyses reported a positive correlation between FBXO32 and PI3K–AKT pathway, identifying pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) as an interacting protein. Mechanistically, DNA promoter hypomethylation elevated FBXO32 expression in HCC cells, promoting K48-linked PHLPP2 polyubiquitination at the K592 and K942 sites through direct interactions. Notably, targeting FBXO32 significantly inhibited tumor growth in both an orthotopic HCC model and an organoid model derived from HCC patients. To sum up, this work emphasizes the part of FBXO32 in propelling HCC progression via facilitating PI3K–AKT pathway activation via PHLPP2 degradation.