Forkhead box protein A1 (FOXA1), also known as hepatocyte nuclear factor 3-alpha (HNF-3A), is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''FOXA1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

Structure

FOXA1 is a member of the forkhead domain transcription factor family. The forkhead domain is essential for its DNA-binding function, and consists of three

alpha helices An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

, three

beta strand The beta sheet (β-sheet, also β-pleated sheet) is a common structural motif, motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone chain, backbon ...

s, and two loops (called "wings"). The domain binds along the DNA major groove and the wings directly contact the DNA. FOXA1 is modified by the

O-GlcNAc ''O''-GlcNAc (short for ''O''-linked GlcNAc or ''O''-linked β-''N''-acetylglucosamine) is a reversible Enzyme, enzymatic post-translational modification that is found on serine and threonine residues of Cell nucleus, nucleoCytoplasm, cytoplasmi ...

post-translational modification In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...

Function

FOXA1 is a pioneer factor, a

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

that directly binds condensed

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...

, facilitating the binding of other transcription factors. In prostate cells, FOXA1 interacts with the

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...

(AR) to drive transcription of prostate-specific genes. FOXA1 is a member of the

forkhead FOX (forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic ...

class of DNA-binding proteins. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver.

Clinical significance

Role in cancer

FOXA1 is one of the most frequently altered genes in prostate cancer, with mutations in the coding sequence of up to 9% of localized prostate cancer cases, and 13% of metastatic treatment-resistant prostate cancers. Most cancer-associated FOXA1 mutations are

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...

s, changing the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

sequence of the

fork head domain The fork head domain is a type of protein domain that is often found in transcription factors and whose purpose is to bind DNA. Function The fork head protein of ''Drosophila melanogaster'', a transcription factor that promotes terminal rathe ...

's DNA-binding sites. Expression of FOXA1 correlates with two EMT markers, namely Twist1 and

E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), is a protein that in humans is encoded by the ''CDH1'' gene (not to be confused with the APC/C activator protein CDH1). Mutations are correlated with Hereditary diffuse gastric cancer, gastric, Here ...

in breast cancer.

Marker in breast cancer

FOXA1 in

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

is highly correlated with

ERα Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the se ...

⁺,

GATA3 GATA3 is a transcription factor that in humans is encoded by the ''GATA3'' gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes. The GATA3 transcription ...

⁺, and PR⁺ protein expression as well as endocrine signaling. FOXA1 acts as a pioneer factor for ERa in ERα⁺ breast cancer, and its expression might identify ERα⁺ cancers that undergo rapid reprogramming of ERa signaling that is associated with poor outcomes and treatment resistance. Conversely, in ERα⁻ breast cancer FOXA1 is highly correlated with low-grade morphology and improved disease free survival. FOXA1 is a downstream target of

in the mammary gland. Expression in ERα⁻ cancers may identify a subset of tumors that is responsive to other endocrine therapies such as

antagonist treatment.

Chemical probe development

Being a transcription factor lacking structurally ordered small molecule-binding sites, FOXA1 has generally been considered to be an undruggable protein. Using a chemical proteomics approach directed against cysteines, researchers from

Scripps Research Scripps Research is a nonprofit American medical research facility that focuses on research and education in the biomedical sciences. Headquartered in San Diego, California, the institute has over 170 laboratories employing 2,100 scientists, tec ...

identified a tryptoline acrylamide chemical probe WX-02-23 that reacts with FOXA1 C258 site-specifically and stereospecifically. WX-02-23 binds FOXA1 in a DNA-dependent manner, and WX-02-23 likewise enhances FOXA1 interaction with DNA.

References

External links

* {{Transcription factors, g3 Forkhead transcription factors