The transcription factor FOXQ1 in cancer

Abstract

FOXQ1 is a member of the large forkhead box (FOX) family of transcription factors that is involved in all aspects of mammalian development, physiology, and pathobiology. FOXQ1 has emerged as a major regulator of epithelial-to-mesenchymal transition and tumour metastasis in cancers, especially carcinomas of the digestive tract. Accordingly, FOXQ1 induction is recognised as an independent prognostic factor for worse overall survival in several types of cancer, including gastric and colorectal cancer. In this review article, I summarise new evidence on the role of FOXQ1 in cancer, with a focus on molecular mechanisms that control FOXQ1 levels and the regulation of FOXQ1 target genes. Unravelling the functions of FOXQ1 has the potential to facilitate the development of targeted treatments for metastatic cancers.

Keywords: Epithelial-to-mesenchymal transition; Forkhead box; Gene regulation; Metastasis; Transcription factor.

Fig. 1

The structure of FOXQ1. A Domain organisation of the human FOXQ1 protein. The prediction of possible acidic transcription activation domains was done in ADpred [10]. DBD: DNA-binding domain; NLS: nuclear localisation sequence. B Predicted structure of human FOXQ1 (AlphaFold model AF-Q9C009-F1). The highly conserved DBD is flanked by disordered N and C-termini. C DNA recognition motif of rat Foxq1 (JASPAR ID MA0040.1), whose DBD is identical to the human protein. D Sequence alignment of the DBD of representative members of all 19 FOX subfamilies. The consensus sequence is shown on top, and conserved residues are highlighted in yellow. The alignment was performed in Clustal Omega [130]

Fig. 2

Altered expression of FOXQ1 in cancer. The bar graphs depict FOXQ1 mRNA levels in selected cancers from The Cancer Genome Atlas (TCGA), compared to normal tissue samples. The TCGA dataset designation is shown in parentheses. TPM: Transcripts per million. The corresponding survival data of patients with cancer were stratified by quartiles, and analysed using the Logrank test. Data were retrieved from and plotted in GEPIA 2 [131]

Fig. 3

Gene regulation by FOXQ1 in colorectal cancer cells. A Volcano plot of differentially expressed genes in HCT116 cells following overexpression of FOXQ1. EMT-associated genes are highlighted. Note, in particular, the significant induction of the core EMT transcription factor SNAI2. FDR: false discovery rate. B Corresponding UpSet plot of significantly enriched gene ontology terms (biological process; FDR-adjusted p-values < 0.05) associated with genes induced by FOXQ1 in HCT116 cells. FOXQ1 induces genes involved in cell motility and extracellular matrix remodelling, which are key features of EMT. Data were taken from dataset E-MTAB-12062 [12] and plotted in R 4.4.0

Fig. 4

Target genes of FOXQ1. Selected target genes of FOXQ1 that are involved in EMT and tumour progression are shown. Targets with evidence for direct regulation by FOXQ1 (e.g., by ChIP or promoter assays) are highlighted with black outlines

Fig. 5

Interactors of FOXQ1. Components of large protein complexes are grouped in grey boxes. MS: mass spectrometry

Fig. 6

Regulators of FOXQ1 expression and stability