The E3 Ubiquitin Ligase Fbxo4 Functions as a Tumor Suppressor: Its Biological Importance and Therapeutic Perspectives

SIMPLE SUMMARY: Fbxo4 is an E3 ubiquitin ligase that requires the formation of a complex with S-phase kinase-associated protein 1 and Cullin1 to catalyze the ubiquitylation of its substrates. Moreover, Fbxo4 depends on the existence of posttranslational modifications and/or co-factor to be activated to perform its biological functions. The well-known Fbxo4 substrates have oncogenic or oncogene-like activities, for example, cyclin D1, Trf1/Pin2, p53, Fxr1, Mcl-1, ICAM-1, and PPARγ; therefore, Fbxo4 is defined as a tumor suppressor. Biologically, Fbxo4 regulates cell cycle progression, DNA damage response, tumor metabolism, cellular senescence, metastasis and tumor cells’ response to chemotherapeutic compounds. Clinicopathologically, the expression of Fbxo4 is associated with patients’ prognosis depending on different tumor types. Regarding to its complicated regulation, more in-depth studies are encouraged to dissect the detailed molecular mechanisms to facilitate developing new treatment through targeting Fbxo4. ABSTRACT: Fbxo4, also known as Fbx4, belongs to the F-box protein family with a conserved F-box domain. Fbxo4 can form a complex with S-phase kinase-associated protein 1 and Cullin1 to perform its biological functions. Several proteins are identified as Fbxo4 substrates, including cyclin D1, Trf1/Pin2, p53, Fxr1, Mcl-1, ICAM-1, and PPARγ. Those factors can regulate cell cycle progression, cell proliferation, survival/apoptosis, and migration/invasion, highlighting their oncogenic or oncogene-like activities. Therefore, Fbxo4 is defined as a tumor suppressor. The biological functions of Fbxo4 make it a potential candidate for developing new targeted therapies. This review summarizes the gene and protein structure of Fbxo4, the mechanisms of how its expression and activity are regulated, and its substrates, biological functions, and clinicopathological importance in human cancers.