FOXO transcription factors in cancer development and therapy

Abstract

The forkhead box O (FOXO) transcription factors are considered as tumor suppressors that limit cell proliferation and induce apoptosis. FOXO gene alterations have been described in a limited number of human cancers, such as rhabdomyosarcoma, leukemia and lymphoma. In addition, FOXO proteins are inactivated by major oncogenic signals such as the phosphatidylinositol-3 kinase pathway and MAP kinases. Their expression is also repressed by micro-RNAs in multiple cancer types. FOXOs are mediators of the tumor response to various therapies. However, paradoxical roles of FOXOs in cancer progression were recently described. FOXOs contribute to the maintenance of leukemia-initiating cells in acute and chronic myeloid leukemia. These factors may also promote invasion and metastasis of subsets of colon and breast cancers. Resistance to treatment was also ascribed to FOXO activation in multiple cases, including targeted therapies. In this review, we discuss the complex role of FOXOs in cancer development and response to therapy.

Keywords: Cancer stem cells; Cell cycle; Cell invasion; FOXO1; FOXO3; FOXO4; Metastasis; Tumor-initiating cells.

Fig. 1

FOXO phosphorylation downstream oncogenic signaling pathways. Schematic representation of the major signaling pathways related to cancer and their link with FOXOs. Three kinases, AKT, ERK and IKK, can phosphorylate FOXOs leading to their inactivation and degradation. These regulations have been demonstrated in several cancer types, as indicated. The phosphorylation site positions correspond to human FOXOs. FOXO1 phosphorylation by ERK has also been suggested [99]. AA amino acids

Fig. 2

FOXO functions in cancer. FOXOs are involved in diverse physiological processes, such as cell cycle arrest, apoptosis, and oncogene-induced senescence, which prevent tumor development and contribute to cancer cell killing by various drugs (green). By contrast, FOXOs also play pro-tumoral roles, in the resistance to certain treatments, for instance (red). Ambiguous functions of FOXOs have been described in angiogenesis, oxidative stress resistance, differentiation, cancer stem cell maintenance and the control of cell invasion and metastasis (orange). Key target genes are indicated in smaller letters. Repressed genes are crossed

Fig. 3

FOXO genomic alterations and mutations. The PAX3/7-FOXO1 fusion protein occurs following a breakpoint at the chromosomal region corresponding to the C-terminal part of PAX3/7 and the forkhead box domain of FOXO1. This generates a fusion protein that contains the PAX DNA-binding domain (corresponding to the paired box and homeodomain), the truncated forkhead box domain and the FOXO1 transactivation domain. The MLL-FOXO3/4 fusion protein corresponds to the DNA-binding domain and DNA methyltransferase domain of MLL fused to the truncated forkhead box domain of FOXO3 or 4 and the transactivation domain. Point mutations have been identified in FOXO1 in non-Hodgkin B-lymphomas

Fig. 4

FOXOs in leukemia. FOXOs are inactivated by AKT and IKK in CML and AML, respectively (left). Tyrosine kinase inhibitors, such as imatinib and nilotinib, reactivate FOXOs in CML to promote apoptosis and cell cycle arrest. In some acute leukemia cases, FOXO3 and FOXO4 are found in fusion protein with MLL (middle panel). FOXOs also play a pro-tumoral role by promoting the self-renewal of LICs (right)