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Forkhead box transcription factors in cancer initiation, progression and chemotherapeutic drug response

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The superfamily of Forkhead box (Fox) proteins is an extensive group of transcription regulators that share an evolutionary conserved ‘winged-helix’ DNA binding motif. Dating back to more than two decades ago, the first Fox protein (fkh) was discovered in the fruitfly, Drosophila Melanogaster which is vital ...

The superfamily of Forkhead box (Fox) proteins is an extensive group of transcription regulators that share an evolutionary conserved ‘winged-helix’ DNA binding motif. Dating back to more than two decades ago, the first Fox protein (fkh) was discovered in the fruitfly, Drosophila Melanogaster which is vital for pattern formation in the developing embryos. In parallel to this discovery, a novel transcription factor, Hepatic Nuclear Factor 3 (HNF3) was cloned and characterised. Strikingly, the two transcription factors were found to be closely related, in particular they have the highest sequence identity at the DNA binding regions. The advent of these pioneering works has identified 19 subgroups of Fox proteins in humans. Most importantly, Fox proteins are pivotal modulators in cell fate decisions with the ability to influence myriad cellular functions including cell proliferation, differentiation, survival, migration, angiogenesis, stress resistance and DNA damage repair. As a result, any deregulation in Fox proteins will tip the balance of cellular homeostasis towards the initiation and progression of cancer. Amongst the Fox proteins, the subfamilies FoxO, FoxM, FoxP, FoxC and FoxA have hitherto been shown to participate in the various aspects of cancer development. Despite having highly similar DNA binding domains and overlapping gene targets, the sub families of the Forkhead family exhibit distinct regulatory roles in the genetic circuitry. The understanding of Fox proteins is further complicated by the occurrence of functionally antagonistic relationship between Fox proteins, such as FoxO3A and FoxM1 in the regulation of common gene targets. Further to this, the fact that different forkhead members can be categorised as tumour suppressors or oncogenes poses difficulty in capturing the complete picture of Fox proteins in tumorigenesis and tumour progression. Of note, recent advances have reported the involvement of Fox proteins in the acquisition of chemotherapeutic drug resistance as well as the reversal of drug resistance in cancers, thus, generating an increased enthusiasm in the quest for agents to target the Fox proteins. Taken together, accumulating evidence has not only confirmed that Fox proteins are key players in tumour biology, but they also possess great potential in opening a therapeutic avenue in cancer.


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