Human forkhead box class O (FoxO) transcription factors, activated in response to a wide range of external
stimuli, like growth factors, insulin, nutrient levels and oxidative stress, are able to control several specific geneexpression
programs. Besides their clear implication in metabolic processes, they appear to play a relevant role in tumour
suppression by upregulation of genes involved in cell cycle arrest or apoptosis. Recent research efforts provide new insights
into the molecular modulation of FoxO in liver cancer and disclose potential opportunities for developing new antitumor
drugs. Through an intricate regulatory model, achieved via several post-translational modifications, including phosphorylation,
acetylation, and ubiquitination, which control their subcellular localization and DNA binding activity, FoxO
factors act as tumour suppressors. Low levels of FoxOs are associated with poor prognosis in cancer patients, and seem to
confer chemotherapy resistance. Within FoxO members, FoxO3a appears to present anti-tumour properties in hepatocellular
carcinoma, inducing the expression of pro-apoptotic genes, or interfering with signaling cascades commonly altered in
this disease such as Wnt/β-catenin, PI3K/AKT/mTOR or MAPKs pathways. Here, we describe the main mechanisms of
FoxO proteins regulation, and their cross-link with altered pathways in liver cancer. Moreover, based on the current
knowledge of FoxO modulation, emphasis is placed on the development of novel agents which specifically activate FoxO
family members and could be useful in the treatment of hepatocarcinoma.
Apoptosis, cancer, FoxO, hepatocarcinoma, liver, MAPK.
Institute of Biomedicine (IBIOMED), Campus Universitario, 24071, Leon, Spain.