FOXA1 (forkhead box A1)

2010-07-01   Harikrishna Nakshatri , Sunil Badve 

Department of Surgery, Biochemistry, Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA (HN); Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA (SB)

Identity

HGNC
LOCATION
14q21.1
IMAGE
Atlas Image
LEGEND
FOXA1 is located on chromosome 14q21.1 and the transcribed region including an intron spans only 5300 bases. This protein binds to chromatinized DNA and, therefore, described as a "pioneer factor".
LOCUSID
ALIAS
HNF3A,TCF3A
FUSION GENES

DNA/RNA

Atlas Image

Description

The transcribed region of FOXA1 extends only to 5400 bases and contains two exons and one intron. This gene is amplified in breast, esophageal, lung, and thyroid carcinomas. No deletions or chromosomal translocations have been reported. MIPOL1 and C14orf25 are the two adjoining genes. MIPOL1 has been described as a tumor suppressor gene in nasopharyngeal carcinoma, whereas the function of C14orf25 is unknown.

Transcription

FOXA1 is expressed predominantly in liver and is highly responsive to hormonal manipulation. Insulin suppresses its expression in embryonic stem cells as well as in breast cancer cells, whereas retinoic acid, estrogen, androgen, and heregulin induce its expression. The developmental transcription factors Oct-4 and SOX4 repress FOXA1 expression, whereas SOX17 and GATA-3 increase its expression. No splice variants have been reported. 542 base long promoter/enhancer is sufficient for liver-specific expression. This region binds to transcription factors TTF1 and NF-1. By binding to its own enhancer/promoter, FOXA1 autoregulates its expression. Peroxisome Proliferator Activated Receptor gamma also upregulates FOXA1 expression, although region of the promoter/enhancer involved in this upregulation is yet to be characterized.

Proteins

Atlas Image

Description

FOXA1 is a 473 amino acid long transcription factor that binds to the consensus sequence A(A/T)TRTT(G/T)RYTY using the central region of the protein. Crystallography showed DNA binding domain in a winged helix-loop-helix configuration. Both N-terminus and C-terminus have transactivation domains. In silico analysis revealed 11 putative acetylation sites; acetylation sites in the DNA binding domain inhibit interaction with chromatin. The N-terminus has a putative caseine kinase 1 phosphorylation site.

Expression

FOXA1 was originally identified as a transcription factor that regulates gene expression in endoderm-derived tissues such as liver and lungs. Subsequent studies showed expression in pancreas, breast, prostate, bladder, intestine, and seminal vesicle. During embryogenesis, expression is seen in tissues derived from both foregut and hindgut endoderm (liver, lung, pancreas, stomach, intestine, prostate, and bladder). Organs derived from ectoderm (forebrain, floor plate, olfactory epithelium) and mesoderm (kidney, vagina, uterus, seminal and coagulating glands) also show expression. FOXA1 along with FOXA2 is required for normal bile duct development as deletion of FOXA1/2 in embryonic liver leads to hyperplasia of the billiary tree. Absence of FOXA1 in mammary gland leads to impaired ductal morphogenesis and reduction in the number of estrogen receptor-positive luminal epithelial cells.

Localisation

FOXA1 is localized predominantly in the nucleus. transforming growth factor beta 1 treatment results in cytoplasmic localization of the protein, which may be dependent on protein kinase C.

Function

FOXA1 binds to chromatinized DNA and opens the chromatin to allow binding of additional transcription factors. Specific histone modification such as histone H3 lysine 4 methylation guides recruitment of other factors. FOXA1 facilitates the recruitment of nuclear receptors including estrogen receptor, androgen receptor and glucocorticoid receptor. FOXA1 binding leads to both activation or repression of genes. These gene-specific effects involve interaction with or recruitment of other transcription factors such as SRC-3, USF2, TLE3, COUP-TFII, SHP, SMAD3, and HDAC7.

Homology

FOXA1 belongs to the 40-member FOX family of transcription factors. FOXA1, FOXA2, and FOXA3 form a subfamily and share a 110 amino acid long DNA binding domain with only 7 amino acid difference.

Mutations

Germinal

Coding region variation Ala83Thr, which is within the N-terminal transactivation domain, has been observed. However, this variation is not linked to breast cancer or maturity onset diabetes.

Implicated in

Entity name
Breast cancer
Disease
Breast cancers that express estrogen receptor and progestrone receptor (ER+/PR+) demonstrate elevated FOXA1 expression. Amplification of the genomic region encompassing FOXA1 is also observed in ER+/PR+ breast cancer. A small subgroup of ER-/PR- negative breast cancers express FOXA1 and ER-/FOXA1- tumors show 3.6 fold enhanced recurrence rate compared to ER-/FOXA1+ tumors.
Prognosis
FOXA1-positivity ER+/PR+ breast cancer is associated with favorable prognosis.
Entity name
Prostate cancer
Disease
FOXA1 is expressed in prostate cancer regardless of Gleason grade score and the expression is higher in metastatic disease. In transgenic animal models of prostate cancer, FOXA1 expression is seen in neuroendocrine carcinomas.
Entity name
Pancreatic cancer
Disease
FOXA1 is expressed in normal and well-differentiated cancer but the expression is lost in undifferentiated cancer cells. Loss of FOXA1 expression correlates with epithelial-to-mesenchymal transition.
Entity name
Esophageal squamous cell carcinoma
Disease
Cancers that have metastasized to lymphnodes express higher levels of FOXA1 along with its target gene KRT7.
Entity name
Anaplastic thyroid carcinoma
Disease
Overexpressed in aggressive thyroid cancers and is amplified in these cancers. FOXA1 increases proliferation of these cells.
Entity name
Diabetes
Disease
FOXA1 deficient mice are growth retarded and hypoglycemic due to defects in insulin secretion. However, the corresponding effects in human have not been reported.
Entity name
Diet restriction-induced longevity
Note
PHA-4, the FOXA1, A2 and A3 ortholog in C. elegans is essential for diet-restriction-induced longevity.

Bibliography

Pubmed IDLast YearTitleAuthors
195493282009Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours.Albergaria A et al
176711242007FOXA1 expression in breast cancer--correlation with luminal subtype A and survival.Badve S et al
196872992009FoxA1 binding directs chromatin structure and the functional response of a glucocorticoid receptor-regulated promoter.Belikov S et al
205015932010FOXA1 is an essential determinant of ERalpha expression and mammary ductal morphogenesis.Bernardo GM et al
155677152004Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues.Besnard V et al
160091312005Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1.Carroll JS et al
181562122008Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer.Chiaverotti T et al
118646022002Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4.Cirillo LA et al
96852611998Regulation of a transcription factor network required for differentiation and metabolism.Duncan SA et al
118913242002The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression.Guo Y et al
191834832009Screening and association testing of common coding variation in steroid hormone receptor co-activator and co-repressor genes in relation to breast cancer risk: the Multiethnic Cohort.Haiman CA et al
192740502009The evolution of Fox genes and their role in development and disease.Hannenhalli S et al
193725802009Genetic alterations and oncogenic pathways associated with breast cancer subtypes.Hu X et al
198974912010Stable chromatin binding prevents FoxA acetylation, preserving FoxA chromatin remodeling.Kohler S et al
110044792000Transforming growth factor-beta(1) regulation of surfactant protein B gene expression is mediated by protein kinase-dependent intracellular translocation of thyroid transcription factor-1 and hepatocyte nuclear factor 3.Kumar AS et al
16721181991Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head.Lai E et al
201817212010Global characterization of transcriptional impact of the SRC-3 coregulator.Lanz RB et al
194361102009Foxa1 and Foxa2 regulate bile duct development in mice.Li Z et al
122349962002The hepatocyte nuclear factor 3 alpha gene, HNF3alpha (FOXA1), on chromosome band 14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas.Lin L et al
183588092008FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription.Lupien M et al
200681692010Prognosis of hormone-dependent breast cancers: implications of the presence of dysfunctional transcriptional networks activated by insulin via the immune transcription factor T-bet.McCune K et al
180036592008SMAD3 prevents binding of NKX2.1 and FOXA1 to the SpB promoter through its MH1 and MH2 domains.Minoo P et al
81876301993Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm.Monaghan AP et al
192611982009FOXA1 in breast cancer.Nakshatri H et al
194707272009FOXA1 is a potential oncogene in anaplastic thyroid carcinoma.Nucera C et al
174762122007PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans.Panowski SH et al
89938361997Hepatocyte nuclear factor-3 alpha promoter regulation involves recognition by cell-specific factors, thyroid transcription factor-1, and autoactivation.Peterson RS et al
200430652010Forkhead box A1 transcriptional pathway in KRT7-expressing esophageal squamous cell carcinomas with extensive lymph node metastasis.Sano M et al
191475882009Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells.Scharer CD et al
179642672007Repression by Groucho/TLE/Grg proteins: genomic site recruitment generates compacted chromatin in vitro and impairs activator binding in vivo.Sekiya T et al
201600412010Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer.Song Y et al
198465362009Upstream stimulatory factor 2, a novel FoxA1-interacting protein, is involved in prostate-specific gene expression.Sun Q et al
180376622008Forkhead box A1 expression in breast cancer is associated with luminal subtype and good prognosis.Thorat MA et al
113557502001Genetic variation in the hepatocyte nuclear factor (HNF)-3alpha gene does not contribute to maturity-onset diabetes of the young in Japanese.Yu L et al

Other Information

Locus ID:

NCBI: 3169
MIM: 602294
HGNC: 5021
Ensembl: ENSG00000129514

Variants:

dbSNP: 3169
ClinVar: 3169
TCGA: ENSG00000129514
COSMIC: FOXA1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000129514ENST00000250448P55317
ENSG00000129514ENST00000553751G3V4B9

Expression (GTEx)

0
10
20
30
40
50
60
70
80

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
160091312005Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1.610
183588092008FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription.457
215724382011Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA.396
211511292011FOXA1 is a key determinant of estrogen receptor function and endocrine response.338
230011242012Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression.180
176167092007Positive cross-regulatory loop ties GATA-3 to estrogen receptor alpha expression in breast cancer.152
160878632005From the Cover: Location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response.150
219150962011Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer.134
217015582011Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1.101
212333992011Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers.97

Citation

Harikrishna Nakshatri ; Sunil Badve

FOXA1 (forkhead box A1)

Atlas Genet Cytogenet Oncol Haematol. 2010-07-01

Online version: http://atlasgeneticsoncology.org/gene/44403/foxa1