Abstract
Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.
Highlights
Metastasis is the process by which cancer cells spread from their origins to secondary sites of the body, often via the bloodstream or the lymphatic system
Research studies to date have pointed to a key tumour-suppressive role for Forkhead box O (FOXO) transcription factors
This is mediated through the ability of FOXOs to regulate genes essential for cell proliferative arrest, cell death, autophagy, senescence, angiogenesis, cell migration and metastasis
Summary
Cancer is a leading cause of death worldwide. It is a group of diseases that can initiate in any tissue or organ when abnormal cells grow uncontrollably and migrate from their original sites to invade other parts of the body. Forkhead box (FOX) proteins are a vast group of transcription factors united by an evolutionarily conserved winged-helix DNA binding domain. The FOX winged-helix structure, reminiscent of a butterfly, consists of three N-terminal α-helices, three β-strands and two loops [3]. Through this unique structural feature, the FOX proteins recognise the cis-regulatory sequences in their target genes to direct gene expression [4]. Despite the FOX proteins possessing highly analogous DNA binding domains, their distinct tissue-specific expression patterns and regulatory mechanisms provide them their dedicated functions [5]. Cancer Metastasis Rev (2020) 39:681–709 against a broad spectrum of developmental and metabolic diseases due to the loss of function of a single-core FOX protein or gene in haploid insufficiency. The misregulation, misexpression and/or mutation of FOX genes can lead to human genetic and metabolic diseases, deregulated ageing and cancer
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