The Dominant Role of Forkhead Box Proteins in Cancer

Abstract

Forkhead box (FOX) proteins are multifaceted transcription factors that are significantly implicated in cancer, with various critical roles in biological processes. Herein, we provide an overview of several key members of the FOXA, FOXC, FOXM1, FOXO and FOXP subfamilies. Important pathophysiological processes of FOX transcription factors at multiple levels in a context-dependent manner are discussed. We also specifically summarize some major aspects of FOX transcription factors in association with cancer research such as drug resistance, tumor growth, genomic alterations or drivers of initiation. Finally, we suggest that targeting FOX proteins may be a potential therapeutic strategy to combat cancer.

Keywords: FOX proteins; FOXA; FOXC; FOXO-FOXM1; FOXP; drug resistance; genomic alterations; hallmarks of cancer; miRNAs.

Figure 1

Direct and indirect associations of 14 individual FOX transcription factors and the hallmarks of cancer acquired from Cancer Hallmarks Analytics Tool. FOXO1 appears to be associated with every hallmark while FOXM1, FOXO3a, FOXA2, and FOXP3 are connected to at least eight hallmarks of cancer. FOXP2 is only related to genome instability when FOXP4 is involved in the genome instability and immune destruction process.

Figure 2

The critical roles of FOXM1 in cancer progression. (A) Integration of extracellular and intracellular signaling pathways with the axis of forkhead box protein M1 and forkhead box class O3a. (B) FOXM1 contributes to chemo-resistance through ABC transporters, tumor growth and cell proliferation through cell-cycle, cancer cell metastasis through matrix metalloproteinases, and DNA damage response through NBS1.