FOXA1 explained

Forkhead box protein A1 (FOXA1), also known as hepatocyte nuclear factor 3-alpha (HNF-3A), is a protein that in humans is encoded by the FOXA1 gene.[1] [2] [3]

Function

FOXA1 is a pioneer factor, a transcription factor that directly binds condensed chromatin, facilitating the binding of other transcription factors.[4] In prostate cells, FOXA1 interacts with the androgen receptor (AR) to drive transcription of prostate-specific genes.[4]

FOXA1 is a member of the forkhead 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.[1]

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, three beta strands, and two loops (called "wings"). The domain binds along the DNA major groove and the wings directly contact the DNA.[5]

FOXA1 is modified by the O-GlcNAc post-translational modification.[6]

Marker in breast cancer

FOXA1 in breast cancer is highly correlated with ERα+, GATA3+, 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.[7] Conversely, in ERα− breast cancer FOXA1 is highly correlated with low-grade morphology and improved disease free survival. FOXA1 is a downstream target of GATA3 in the mammary gland.[8] Expression in ERα− cancers may identify a subset of tumors that is responsive to other endocrine therapies such as androgen receptor antagonist treatment.[9] [10]

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.[4] Most cancer-associated FOXA1 mutations are missense mutations, changing the amino acid sequence of the fork head domain's DNA-binding sites.[4]

Expression of FOXA1 correlates with two EMT markers, namely Twist1 and E-cadherin in breast cancer.[11]

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 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.[12]

Notes and References

  1. Web site: Entrez Gene: forkhead box A1.
  2. Bingle CD, Gowan S . Molecular cloning of the forkhead transcription factor HNF-3 alpha from a human pulmonary adenocarcinoma cell line . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1307 . 1 . 17–20 . June 1996 . 8652662 . 10.1016/0167-4781(96)00058-9 .
  3. Mincheva A, Lichter P, Schütz G, Kaestner KH . Assignment of the human genes for hepatocyte nuclear factor 3-alpha, -beta, and -gamma (HNF3A, HNF3B, HNF3G) to 14q12-q13, 20p11, and 19q13.2-q13.4 . Genomics . 39 . 3 . 417–419 . February 1997 . 9119385 . 10.1006/geno.1996.4477 .
  4. Teng M, Zhou S, Cai C, Lupien M, He HH . Pioneer of prostate cancer: past, present and the future of FOXA1 . Protein Cell . 12 . 1 . 29–38 . January 2021 . 32946061 . 7815845 . 10.1007/s13238-020-00786-8 .
  5. Martin EM, Orlando KA, Yokobori K, Wade PA . The estrogen receptor/GATA3/FOXA1 transcriptional network: lessons learned from breast cancer . Curr Opin Struct Biol . 71 . 65–70 . December 2021 . 34225008 . 8648900 . 10.1016/j.sbi.2021.05.015 .
  6. Liu . Yajie . Yu . Kairan . Kong . Xiaotian . Zhang . Keren . Wang . Lingyan . Zhang . Nana . Chen . Qiushi . Niu . Mingshan . Li . Wenli . Zhong . Xiaomin . Wu . Sijin . Zhang . Jianing . Liu . Yubo . 2023-08-18 . FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer . Science Advances . en . 9 . 33 . eadg7112 . 10.1126/sciadv.adg7112 . 2375-2548 . 10438466 . 37595040. 2023SciA....9G7112L .
  7. Ross-Innes CS, Stark R, Teschendorff AE, Holmes KA, Ali HR, Dunning MJ, Brown GD, Gojis O, Ellis IO, Green AR, Ali S, Chin SF, Palmieri C, Caldas C, Carroll JS . 6 . Differential oestrogen receptor binding is associated with clinical outcome in breast cancer . Nature . 481 . 7381 . 389–393 . January 2012 . 22217937 . 3272464 . 10.1038/nature10730 . 2012Natur.481..389R .
  8. Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z . GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland . Cell . 127 . 5 . 1041–1055 . December 2006 . 17129787 . 2646406 . 10.1016/j.cell.2006.09.048 .
  9. Albergaria A, Paredes J, Sousa B, Milanezi F, Carneiro V, Bastos J, Costa S, Vieira D, Lopes N, Lam EW, Lunet N, Schmitt F . 6 . Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours . Breast Cancer Research . 11 . 3 . R40 . 2009 . 19549328 . 2716509 . 10.1186/bcr2327 . free .
  10. Sanga S, Broom BM, Cristini V, Edgerton ME . Gene expression meta-analysis supports existence of molecular apocrine breast cancer with a role for androgen receptor and implies interactions with ErbB family . BMC Medical Genomics . 2 . 59 . September 2009 . 19747394 . 2753593 . 10.1186/1755-8794-2-59 . free .
  11. BenAyed-Guerfali D, Dabbèche-Bouricha E, Ayadi W, Trifa F, Charfi S, Khabir A, Sellami-Boudawara T, Mokdad-Gargouri R . 6 . Association of FOXA1 and EMT markers (Twist1 and E-cadherin) in breast cancer . Molecular Biology Reports . 46 . 3 . 3247–3255 . June 2019 . 30941644 . 10.1007/s11033-019-04784-w . 91190545 .
  12. Won . Sang Joon . Zhang . Yuxiang . Reinhardt . Christopher J. . Hargis . Lauren M. . MacRae . Nicole S. . DeMeester . Kristen E. . Njomen . Evert . Remsberg . Jarrett R. . Melillo . Bruno . Cravatt . Benjamin F. . Erb . Michael A. . November 2024 . Redirecting the pioneering function of FOXA1 with covalent small molecules . Molecular Cell . en . 84 . 21 . 4125–4141.e10 . 10.1016/j.molcel.2024.09.024. 39413792 .

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