The Diverse Consequences of FOXC1 Deregulation in Cancer

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.

Keywords: cellular reprogramming; epigenetics; epithelial-mesenchymal transition; metastasis; pioneer factor; transcription factor.

Figure 1

(Above) Overview of FOXC1 protein structure and functional protein domains identified by in vitro analyses. (Below) Amino acid sequence alignment of critical residues in the Forkhead domain of FOXC1 which are essential for the DNA-binding properties of FOX proteins. Residues highlighted in orange are indispensable for sequence-specific recognition of the FOX DNA motif, while those highlighted in blue promote non-specific engagement of nucleosomal DNA by FOXA proteins, consistent with pioneer activity [10,11]. AD, activating domain; DBD, Forkhead DNA-binding domain; ID, inhibitory domain; NLS, nuclear localization signal; hs, Homo sapiens.

Figure 2

A summary of known pre-/post-transcriptional and post-translational processes regulating FOXC1 in cancer. Across several malignancies, deregulation of diverse membrane-associated receptors by mutation and/or overexpression leads to hyperactivation of the MAPK and PI3K signaling pathways and frequent induction of FOXC1 transcription via downstream TFs including AP-1 and NF-κB. In hypoxic tumors, activation of HIF-1α may further stimulate FOXC1 expression. These processes may occur in parallel with loss of PRC2 or BRCA1/GATA3-mediated repression of FOXC1 through currently unclear mechanisms. FOXC1 mRNA may be further regulated through the action of ncRNAs including FOXCUT and miR-204/miR-495 which enhance or impede translation into FOXC1 protein, respectively. Finally, the transcriptional activity and stability of FOXC1 protein may be modulated by partitioning in the nuclear cytoskeleton, or by post-translational modifications including phosphorylation and SUMOylation, although the contribution made by these processes to cancer-specific functionality of FOXC1 remains unclear.