Alternative titles; symbols
HGNC Approved Gene Symbol: FOXA1
Cytogenetic location: 14q21.1 Genomic coordinates (GRCh38): 14:37,589,552-37,595,249 (from NCBI)
The hepatocyte nuclear factors (see HNF1A, 142410) are transcriptional activators for liver-specific transcripts such as albumin and transthyretin. The HNF3 family, including HNF3A, HNF3B (600288), and HNF3G (602295), are members of the forkhead class of DNA-binding proteins (Kaestner et al., 1994).
Kaestner et al. (1994) cloned the mouse Hnf3a, Hnf3b, and Hnf3g genes. The genes encode polypeptides of 468, 459, and 354 amino acids, respectively. Both Hnf3a and Hnf3b are expressed in tissues of endodermal origin, i.e., stomach, intestines, liver, and lung, whereas Hnf3g is more extensively expressed, being present additionally in ovary, testis, heart, and adipose tissue, but missing from lung.
Bingle and Gowan (1996) cloned human HNF3A cDNA from an adenocarcinoma cell line cDNA library using probes specific for rat HNF3A and HNF3B. The predicted 473-amino acid human protein is 82% identical to rat HNF3A. On Northern blots, HNF3A is expressed as an approximately 3-kb mRNA.
The transcription factors Hnf3a and Gata4 (600576) are the earliest known to bind the albumin gene enhancer in liver precursor cells in mouse embryos. To determine how they access sites in silent chromatin, Cirillo et al. (2002) assembled nucleosome arrays containing albumin enhancer sequences and compacted them with linker histone. Hnf3a and Gata4, but not human NF1 (see 600727), mouse Cebp-beta (189965), or yeast GAL4-AH, bound their sites in compacted chromatin and opened the local nucleosomal domain in the absence of ATP-dependent enzymes. The authors showed that the ability of Hnf3a to open chromatin is mediated by a high-affinity DNA-binding site and by the C-terminal domain of the protein, which binds histones H3 and H4. They concluded that factors that potentiate transcription in development are inherently capable of initiating chromatin opening events.
Genomic amplification is observed in many types of human malignancy and is 1 of the mechanisms for the activation of dominant-acting oncogenes in tumorigenesis. Lin et al. (2002) identified 3 amplified restriction fragments in an esophageal adenocarcinoma. These fragments were cloned, sequenced, and mapped to chromosome 14q13. Lin et al. (2002) reported that the frequency of 14q13 amplification was 6.7% in esophageal tumors, and that the amplicon spanned more than 6 Mb in 1 tumor but was contained in a region less than 0.3 Mb in all remaining amplified tumors. Gene amplification of HNF3A was detected in 2 of 5 overexpressed lung tumors examined. Amplification of HNF3A in esophageal and lung tumors suggested a potential oncogenic role for this gene in tumorigenesis.
Lee et al. (2005) showed that Foxa1 and Foxa2 (600288) are required in concert for hepatic specification in mouse. In embryos deficient for both genes in the foregut endoderm, no liver bud was evident and expression of the hepatoblast marker alpha-fetoprotein (AFP; 104150) was lost. Furthermore, Foxa1/Foxa2-deficient endoderm cultured in the presence of exogenous fibroblast growth factor-2 (FGF2; 134920) failed to initiate the expression of the liver markers albumin and transthyretin (176300). Thus, Lee et al. (2005) concluded that Foxa1 and Foxa2 are required for the establishment of competence within the foregut endoderm and the onset of hepatogenesis.
By genomewide analysis, Laganiere et al. (2005) identified 153 promoters bound by estrogen receptor-alpha (ESR1; 133430) in the breast cancer (see 114480) cell line MCF-7 in the presence of estradiol. One was the promoter for FOXA1, whose expression correlated with ESR1 expression in breast tumors. Knockdown of FOXA1 with small interfering RNA in MCF-7 cells suppressed ESR1 binding to the prototypic TFF1 (113710) promoter (which contains a FOXA1 binding site), hindered induction of TFF1 expression by estradiol, and prevented hormone-induced reentry into the cell cycle.
In the nematode C. elegans, the transcription factor PHA4 has an essential role in the embryonic development of the foregut and is orthologous to genes encoding the mammalian family of Foxa transcription factors, Foxa1, Foxa2, and Foxa3 (602295). Foxa family members have important roles during development, but also act later in life to regulate glucagon production and glucose homeostasis, particularly in response to fasting. Panowski et al. (2007) described a newly discovered, adult-specific function for PHA4 in the regulation of diet restriction-mediated longevity in C. elegans. The role of PHA4 in life span determination is specific for dietary restriction, because it is not required for the increased longevity caused by other genetic pathways that regulate aging.
Using genomewide positional analysis with LNCaP prostate cancer cells and MCF-7 cells, Lupien et al. (2008) showed that the cell type-specific functions of FOXA1 relied primarily on differential recruitment of FOXA1 to chromatin predominantly at distant enhancers rather than proximal promoters. This differential recruitment led to cell type-specific changes in chromatin structure and functional collaboration with lineage-specific transcription factors. Differential binding of FOXA1 to chromatin sites was dependent on the distribution of H3 lys4 dimethylation.
Gao et al. (2008) found that Foxa1 and Foxa2 co-occupied multiple regulatory domains in the mouse Pdx1 gene (IPF1; 600733) gene, which is required for pancreatic development. Compound conditional ablation of both Foxa1 and Foxa2 in mouse pancreatic primordium resulted in complete loss of Pdx1 expression, severe pancreatic hypoplasia, disrupted acinar and islet development, hyperglycemia, and death shortly after birth. Foxa1 and Foxa2 predominantly occupied a distal enhancer over 6-kb upstream of the transcriptional start site in the Pdx1 gene, and their occupation of the proximal Pdx1 enhancer was developmentally regulated. Gao et al. (2008) concluded that regulation of PDX1 by FOXA1 and FOXA2 is a key early event controlling expansion and differentiation of the pancreatic primordia.
Using breast cancer and other cancer cell lines, Hurtado et al. (2011) showed that FOXA1 mediated estrogen receptor (ER) binding and function. Almost all ER-chromatin interactions and gene expression changes depended on FOXA1, and FOXA1 influenced genomewide chromatin accessibility. FOXA1 was also required for the inhibitory activity of tamoxifen against ER.
N-acylethanolamines (NAEs) are lipid-derived signaling molecules, which include the mammalian endocannabinoid arachidonoyl ethanolamide. Given its involvement in regulating nutrient intake and energy balance, the endocannabinoid system is an excellent candidate for a metabolic signal that coordinates the organismal response to dietary restriction and maintains homeostasis when nutrients are limited. Lucanic et al. (2011) identified NAEs in C. elegans and showed that NAE abundance is reduced under dietary restriction and that NAE deficiency is sufficient to extend life span through a dietary restriction mechanism requiring PHA4. Conversely, dietary supplementation with the nematode NAE eicosapentaenoyl ethanolamide not only inhibited dietary restriction-induced life span extension in wildtype worms, but also suppressed life span extension in a TOR (see 601231) pathway mutant. Lucanic et al. (2011) concluded that their study demonstrated a role for NAE signaling in aging and indicated that NAEs represent a signal that coordinates nutrient status with metabolic changes that ultimately determine life span.
Wang et al. (2011) presented evidence that cell lineage-specific factors, such as FoxA1, can simultaneously facilitate and restrict key regulated transcription factors, exemplified by the androgen receptor (AR; 313700), to act on structurally and functionally distinct classes of enhancer. Consequently, FoxA1 downregulation, an unfavorable prognostic sign in certain advanced prostate tumors, triggers dramatic reprogramming of the hormonal response by causing a massive switch in AR binding to a distinct cohort of preestablished enhancers. These enhancers are functional, as evidenced by the production of enhancer-templated noncoding RNA (called eRNA by Wang et al., 2011) based on global nuclear run-on sequencing (GRO-seq) analysis, with a unique class apparently requiring no nucleosome remodeling to induce specific enhancer-promoter looping and gene activation. GRO-seq data also suggested that liganded AR induces both transcription initiation and elongation. Wang et al. (2011) concluded that their findings revealed a large repository of active enhancers that can be dynamically tuned to elicit alternative gene expression programs, which may underlie many sequential gene expression events in development, cell differentiation, and disease progression.
Using a chromatin immunoprecipitation-sequencing assay, Gao et al. (2020) showed that LSD1 (KDM1A; 609132) interacted with FOXA1 and active enhancer marks in human prostate cancer cells and that LSD1 inhibition disrupted global FOXA1 chromatin binding. LSD1 positively regulated FOXA1 chromatin binding by demethylating K270 of FOXA1. Through this mechanism, LSD1 maintained enhancer accessibility to AR and regulated AR chromatin binding and transcriptional output. Lsd1 inhibitors repressed xenograft tumor growth in castrated mice by blocking Foxa1 K270 demethylation. Further analysis suggested that the efficacy of Lsd1 inhibitors on tumor suppression correlated with expression levels of Foxa1 and that Lsd1 inhibitors acted in synergy with Ar antagonist treatment.
Mincheva et al. (1997) used fluorescence in situ hybridization to map HNF3A to human chromosome 14q12-q13. This chromosomal region contains a cluster of forkhead domain transcription factors including FKHL1 (164874) and FKHL2. By analysis of RFLPs in interspecific backcross mice, Avraham et al. (1992) mapped the mouse Hnf3-alpha gene to chromosome 12.
Employing a new methodology that combines cistromics, epigenomics, and genotype imputation, Cowper-Sal-lari et al. (2012) annotated the noncoding regions of the genome in breast cancer (see 114480) cells and systematically identified the functional nature of SNPs associated with breast cancer risk. Their results showed that breast cancer risk-associated SNPs are enriched in the cistromes of FOXA1 and ESR1 (133430) and the epigenome of histone H3 lysine-4 monomethylation (H3K4me1) in a cancer- and cell type-specific manner. Furthermore, the majority of the risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, thereby resulting in allele-specific gene expression, which is exemplified by the effect of the rs4784227 SNP in the TOX3 gene (611416) within the 16q12.1 risk locus.
Barbieri et al. (2012) sequenced the exomes of 112 prostate tumor (see 176807) and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 (300188) and FOXA1. SPOP (602650) was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6 to 15% of tumors across multiple independent cohorts. Prostate tumors with mutant SPOP lacked ETS family (see 164720) gene rearrangements and showed a distinct pattern of genomic alterations. Barbieri et al. (2012) concluded that SPOP mutations may define a novel molecular subtype of prostate cancer.
Adams et al. (2019) annotated the landscape of FOXA1 mutations from 3,086 human prostate cancers and defined 2 hotspots in the forkhead domain: the Wing2 region (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations were detected in adenocarcinomas at all stages, whereas R219 mutations were enriched in metastatic tumors with neuroendocrine histology. Interrogation of the biologic properties of wildtype FOXA1 and 14 FOXA1 mutants revealed gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wildtype FOXA1, promoted an exaggerated proluminal differentiation program, whereas 2 different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wildtype FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, noncanonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Adams et al. (2019) concluded that FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression.
Parolia et al. (2019) assembled an aggregate cohort of 1,546 prostate cancers and showed that FOXA1 alterations fall into 3 structural classes that diverge in clinical incidence and genetic coalteration profiles, with a collective prevalence of 35%. Class 1 activating mutations originated in early prostate cancer without alterations in ETS or SPOP, selectively recurred within the wing2 region of the DNA-binding forkhead domain, enabled enhanced chromatin mobility and binding frequency, and strongly transactivated a luminal AR program of prostate oncogenesis. By contrast, class 2 activating mutations were acquired in metastatic prostate cancers, truncated the C-terminal domain of FOXA1, enabled dominant chromatin binding by increasing DNA affinity and, through TLE3 (600190) inactivation, promoted metastasis driven by the WNT pathway. Finally, class 3 genomic rearrangements were enriched in metastatic prostate cancers, consisted of duplications and translocations within the FOXA1 locus, and structurally repositioned a conserved regulatory element, herein denoted FOXA1 mastermind (FOXMIND), to drive overexpression of FOXA1 or other oncogenes. Parolia et al. (2019) concluded that their study reaffirmed the central role of FOXA1 in mediating oncogenesis driven by the androgen receptor, and provided mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer.
Using a conditional knockout model to eliminate Foxa1 and Foxa2 in liver after initial hepatic specification in mouse embryos, Li et al. (2009) found that Foxa1 and Foxa2 were required for bile duct formation at a later stage of liver development. In the absence of Foxa1 and Foxa2 (600288), embryonic liver showed hyperplasia of the biliary tree that was due, at least in part, to activation of Il6 (147620) expression, a proliferative signal for cholangiocytes.
Sekiya and Suzuki (2011) screened the effects of 12 candidate factors to identify 3 specific combinations of 2 transcription factors, comprising Hnf4-alpha (600281) plus Foxa1, Foxa2, or Foxa3 (602295), that can convert mouse embryonic and adult fibroblasts into cells that closely resemble hepatocytes in vitro. The induced hepatocyte-like (iHep) cells had multiple hepatocyte-specific features and reconstituted damaged hepatic tissues after transplantation.
Li et al. (2012) noted that hepatocellular carcinoma (HCC; 114550) is sexually dimorphic in both rodents and humans, with significantly higher incidence in males due to differences in sex hormones. They found that diethylnitrosamine induced liver cancer in both male and female mice with liver-specific deletion of Foxa1 and Foxa2. Coregulation of target genes by Foxa1 and Foxa2 and either Esr1 or Ar was increased during hepatocarcinogenesis in normal female or male mice, respectively, but was lost in Foxa1/Foxa2-deficient mice. Li et al. (2012) concluded that both estrogen-dependent resistance and androgen-mediated facilitation of HCC depend on FOXA1 and FOXA2.
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