Abstract
Forkhead box C1 (FOXC1) is a transcription factor with essential roles in mesenchymal lineage specification and organ development during normal embryogenesis. In keeping with these developmental properties, mutations that impair the activity of FOXC1 result in the heritable Axenfeld-Rieger Syndrome and other congenital disorders. Crucially, gain of FOXC1 function is emerging as a recurrent feature of malignancy; FOXC1 overexpression is now documented in more than 16 cancer types, often in association with an unfavorable prognosis. This review explores current evidence for FOXC1 deregulation in cancer and the putative mechanisms by which FOXC1 confers its oncogenic effects.
Highlights
Forkhead box C1 (FOXC1) is a transcription factor with essential roles in mesenchymal lineage specification and organ development during normal embryogenesis
The Forkhead domain is unique among DNA-binding domains in that its structure is similar to that of the linker histones H1 and H5
This endows Forkhead family members (e.g., FOXA, FOXO and FOXE) with a specialized ability to directly engage DNA in compacted chromatin [6,7,8,9] allowing so-called pioneer activity: the ‘scanning’ of compacted chromatin, identification of target binding sites and direct promotion of nucleosome destabilization to allow other non-pioneer transcription factors to bind to consensus sites nearby
Summary
FOXC1 (previously referred to as FREAC3 or FKHL7) is a single exon gene mapping to chromosome 6p25.3 in humans which encodes a single isoform 553 amino acid protein [1,2] (Figure 1). The Forkhead domain is unique among DNA-binding domains in that its structure is similar to that of the linker histones H1 and H5 (which are involved in generation of a compacted higher order chromatin structure) This endows Forkhead family members (e.g., FOXA, FOXO and FOXE) with a specialized ability to directly engage DNA in compacted chromatin [6,7,8,9] allowing so-called pioneer activity: the ‘scanning’ of compacted chromatin, identification of target binding sites and direct promotion of nucleosome destabilization to allow other non-pioneer transcription factors to bind to consensus sites nearby. SUMOylation of FOXC1 was found to inhibit its transcriptional activity without affecting subcellular localization or protein stability [19]. FOXC1 ID, the functional significance of these sites is less well understood
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