Laissue Molecular Cancer (2019) 18:5 https://doi.org/10.1186/s12943-019-0938-x REVIEW Open Access The forkhead-box family of transcription factors: key molecular players in colorectal cancer pathogenesis Paul Laissue Abstract Colorectal cancer (CRC) is the third most commonly occurring cancer worldwide and the fourth most frequent cause of death having an oncological origin. It has been found that transcription factors (TF) dysregulation, leading to the significant expression modifications of genes, is a widely distributed phenomenon regarding human malignant neoplasias. These changes are key determinants regarding tumour’s behaviour as they contribute to cell differentiation/proliferation, migration and metastasis, as well as resistance to chemotherapeutic agents. The forkhead box (FOX) transcription factor family consists of an evolutionarily conserved group of transcriptional regulators engaged in numerous functions during development and adult life. Their dysfunction has been associated with human diseases. Several FOX gene subgroup transcriptional disturbances, affecting numerous complex molecular cascades, have been linked to a wide range of cancer types highlighting their potential usefulness as molecular biomarkers. At least 14 FOX subgroups have been related to CRC pathogenesis, thereby underlining their role for diagnosis, prognosis and treatment purposes. This manuscript aims to provide, for the first time, a comprehensive review of FOX genes’ roles during CRC pathogenesis. The molecular and functional characteristics of most relevant FOX molecules (FOXO, FOXM1, FOXP3) have been described within the context of CRC biology, including their usefulness regarding diagnosis and prognosis. Potential CRC therapeutics (including genome-editing approaches) involving FOX regulation have also been included. Taken together, the information provided here should enable a better understanding of FOX genes’ function in CRC pathogenesis for basic science researchers and clinicians. Keywords: Colorectal cancer, Forkhead transcription factors, Molecular aetiology Background precursor lesions leading to most cases of CRC [5]. CRC Colorectal cancer (CRC) is a public health concern as it has to be considered a complex disease resulting from a accounts for over 9% of all cancer incidence, representing combination of environmental factors, genetic/epigenetic > 1.4 million of new cases per year [1, 2]. It is the third predisposing variants and specific molecular mechanisms. most commonly occurring cancer worldwide and the Three molecular pathways have been defined as major fac- fourth most frequent cause of death having an oncological tors contributing to CRC carcinogenesis: microsatellite in- origin [3]. Several risk factors have been related to CRC, stability (MSI), chromosomal instability (CIN) and the such as inflammatory bowel disease, antecedents of CRC CpG island methylator phenotype (CIMP) [6, 7]. in first-degree relatives, increased body mass index, The dysfunction of several genes in sporadic and fa- cigarette smoking, little physical activity and particular milial cases has been associated with the disease’s aeti- dietary habits [4]. Adenomas of the colon, which can be ology, such as KRAS, BRAF, c-Src, c-Myc, APC, TP53, conventional adenomas or sessile serrated polyps, are the PIK3CA, MSH2, MLH1, STK11, MSH6, PMS2, APC, CACNA1G, CDKN2A, IGF2, NEUROG1, RUNX3 and Correspondence: [email protected] SOCS1 [8, 9]. Some of these are currently used as clinic- Center For Research in Genetics and Genomics-CIGGUR, GENIUROS Research ally useful prognostic and therapeutic biomarkers [10]; Group, School of Medicine and Health Sciences, Universidad del Rosario, indeed, since CRC development may take years, its early Carrera 24 N° 63C-69, Bogotá, Colombia © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Laissue Molecular Cancer (2019) 18:5 Page 2 of 13 detection and the use of biochemical and molecular/ transcriptional regulators engaged in numerous func- genetic diagnostic tools is a keystone for improving sur- tions during development and adult life; their dysfunc- vival rates. tion has been associated with human diseases [36–42]. The evolution of omics sciences’ experimental proce- Several FOX gene subgroup transcriptional distur- dures during the last few years has led to new cancer bances, affecting numerous complex molecular cas- classifications based on particular molecular findings cades, have been linked to a wide range of cancer types underlying tumour’s biology [11–13]. For instance, highlighting their potential usefulness as molecular bio- immune-MSI, canonical-CMS2, metabolic-CMS3 and markers [23, 41–49]. At least 14 FOX subgroups have mesenchymal-CMS4 CRC subtypes have been proposed been related to CRC pathogenesis, thereby underlining based on transcriptomic differences between tumours their role for diagnosis, prognosis and treatment purposes. which should improve the disease’s diagnosis/prognosis/ This manuscript aims to provide, for the first time, a treatment. Interestingly, it has been found that transcrip- comprehensive review of FOX genes’ roles during CRC tion factor (TF) dysregulation, mainly due to chromo- pathogenesis. The molecular and functional characteris- somal deletion/translocation/amplification and point tics of most relevant FOX molecules have been de- mutations, is a widely distributed phenomenon regard- scribed within the context of CRC biology, including ing human malignant neoplasias [14–16]. TF dysregula- their usefulness regarding diagnosis and prognosis. Po- tion can lead to the significant expression modifications tential CRC therapeutics (including genome-editing ap- of genes involved in various complex biological pro- proaches) involving FOX regulation have also been cesses, such as cell identity determination, proliferation included. Taken together, the information provided here regulation and cell signalling for controlling machinery should enable a better understanding of FOX genes’ in response to micro-environmental signals [17]. These function in CRC pathogenesis for basic science re- changes are key determinants regarding tumour’s behav- searchers and clinicians. iour as they contribute to cell differentiation/prolifera- tion, migration and metastasis, as well as resistance to Main text chemotherapeutic agents. The FOX family of transcription factors: an overview Since the first association was made between DNA The first report of a FOX gene was published in the late regulatory regions and phenotypic variation in bacteria, 1980s when a mutant model of Drosophila melanogaster considerable efforts and advances have been made to was described as having a transformation of the foregut understand TFs’ genomic regulation, such as reporting resembling a head-like structure [50, 51]. Since then, at new gene families, identifying genetic and epigenetic least 50 additional members, which have been classified in molecular modulatory mechanisms, describing expres- 19 subgroups (FOXA to FOXS), have been discovered in sion profiles and programmes regarding numerous cell human species [37, 40, 52–54]. All FOX members share a types, studying the evolution of genetic networks, devel- highly conserved ~ 100 residue DBD (the forkhead do- oping omics data analysis and characterising variations main, FOX-DBD) which was first identified in Drosophila on regulatory motifs and TF mutations in human forkhead and mammalian HNF-3a (FOXA1), HNF-3b disease-related encoding regions [15, 18–31]. TFs have (FOXA2), HNF-3c (FOXA3) proteins [50, 52, 55]. The been classically organised into families and subfamilies, FOX-DBD binds to a target genes’ core sequence depending on the sequence/structure of their DNA (5′-(G/A)(T/C)(A/C)AA(C/T)A-3′) located on the binding domain (DBD) [29]. The total amount of TFs promoter regions [38]. Sequences adjacent to the core has not yet been precisely stated; however, at least 1400 TFBS are also important for TF differential affinity have high confidence sequence-specific DBD [20]. and functions [56–58]. Structurally, the FOX-DBD Mechanistically TFs recognise 6–12 bp-long DNA se- consists of three N-ter α-helices, three β-strands and quences located on target gene promoters/enhancers to two loops, resembling butterfly wings or a “winged regulate expression. These motifs, known as transcrip- helix” [38, 59, 60]. However, some FOX-DBD have tion factor binding sites (TFBS), provide specificity for some modifications in their secondary structure com- binding and their occupancy has been related to several position and topological arrangements [60] (and refer- variables such as quantity, affinity and availability of ences therein). It has been shown that the wings regulatory complexes in specific regions [28, 32]. TFs contribute to regulating DNA binding specificity and bind to other proteins (e.g. cofactors) to form macro- affinity [61]. molecular complexes which are essential elements for Several post-translational modifications,