Regulation of FOXO protein stability via ubiquitination and proteasome degradation

Forkhead box O-class (FOXO) proteins are evolutionally conserved transcription factors. They belong to a family of proteins consisting of FOXO1, FOXO3a, FOXO4 and FOXO6 in humans. Increasing evidence suggests that FOXO proteins function as tumor suppressors by transcriptionally regulating expression of genes involved in cell cycle arrest, apoptosis, DNA repair and oxidative stress resistance. Activation of various protein kinases, including Akt, IκB kinase (IKK) and ERK, leads to phosphorylation of FOXO proteins and their ubiquitination mediated by E3 ligases such as SKP2 and MDM2 in human primary tumors and cancer cell lines. As a result, the tumor suppressor functions of FOXO proteins are either diminished or abrogated due to their ubiquitination-proteasome degradation, thereby favoring cell transformation, proliferation and survival. Thus, ubiquitination and proteasome degradation of FOXO proteins play an important role in tumorigenesis and represent a viable target for cancer treatment. This article is part of a Special Issue entitled: PI3K-AKT-FoxO axis in cancer and aging.