FOXO transcription factor family in cancer and metastasis
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FOXO transcription factor family in cancer and metastasis Yannasittha Jiramongkol 1 & Eric W.-F. Lam 1
# The Author(s) 2020
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 posttranscriptional 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. Keywords Forkhead . Transcription factor . Cancer metastasis . Tumour suppressor . Post-translational regulation . Protein interactions
1 Introduction 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. 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. In most cases, metastatic cancer cannot be cured by treatment. Because of this, metastasis is the major cause of cancer mortality and is responsible for over 90% of cancer deaths [1]. Forkhead box (FOX) proteins are a vast group of transcription factors united by an evolutionarily conserved winged-helix DNA binding domain. FOXOs (forkhead box proteins of class O subgroup) are considered to be tumour suppressors by * Eric W.-F. Lam [email protected] 1
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
virtue of their established functions in cell cycle arrest, apoptosis, sen
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