Deciphering the role of forkhead transcription factors in cancer therapy

Abstract

Forkhead O transcription factors (FOXO) are critical for the regulation of cell cycle arrest, cell death, and DNA damage repair. Inactivation of FOXO proteins may be associated with tumorigenesis, including breast cancer, prostate cancer, glioblastoma, rhabdomyosarcoma, and leukemia. Accumulated evidence shows that activation of oncogenic pathways such as phosphoinositide-3-kinase/AKT/IKK or RAS/mitogen-activated protein kinase suppresses FOXO transcriptional activity through the phosphorylation of FOXOs at different sites that ultimately leads to nuclear exclusion and degradation of FOXOs. In addition, posttranslational modifications of FOXOs such as acetylation, methylation and ubiquitination also contribute to modulating FOXO3a functions. Several anti-cancer drugs like paclitaxel, imatinib, and doxorubicin activate FOXO3a by counteracting those oncogenic pathways which restrain FOXOs functions. In this review, we will illustrate the regulation of FOXOs and reveal potential therapeutics that target FOXOs for cancer treatment.

Fig. (1). Transcriptional regulation by FOXO3a

FOXO3a modulates proliferation, DNA repair, oxidative stress, apoptosis, metabolism and stem cell maintenance through upregulation of several its downstream targets. For instance, FOXO3a negatively control cell proliferation through transcriptional upregulation of p27^KIP1 and promotes cell apoptosis by upregulating pro-apoptotic genes FAS ligand and Bim.

Fig. (2). Inhibition of FOXO3a through three oncogenic kinases

Upon EGF or TNF stimulation, PI3K/AKT, IKKβ and RAS/ERK pathways are activated. The primary oncogenic kinases AKT, IKKβ and ERK directly phosphorylate FOXO3a at different sites and lead to FOXO3a nuclear exclusion. FOXO3a in the cytoplasm loses its anti-tumor activity and is degraded via ubiquitin-proteosome pathway.