Affinage

FOXA1

Hepatocyte nuclear factor 3-alpha · UniProt P55317

Length
472 aa
Mass
49.1 kDa
Annotated
2026-06-09
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOXA1 is a pioneer transcription factor that opens compacted chromatin to license recruitment of steroid hormone receptors and to specify lineage-specific gene-expression programs across mammary, prostate, lung, intestinal, pancreatic, and urothelial tissues (PMID:21151129, PMID:15668254, PMID:19737569, PMID:20534694). It establishes the genome-wide chromatin-binding landscape of estrogen receptor (almost all ERα–chromatin interactions depend on FOXA1) and reciprocally controls androgen-receptor and glucocorticoid-receptor cistromes in a cell-type- and receptor-specific manner; FOXA1 and AR can physically interact through the AR DNA-binding domain, enabling mutual recruitment to sites lacking a cognate motif (PMID:21151129, PMID:23269278, PMID:16467259). Its pioneering capacity rests on a forkhead DNA-binding domain together with N- and C-terminal intrinsically disordered regions that drive condensate formation and dissolution of condensed chromatin (PMID:38101414). Beyond licensing receptors, FOXA1 displays a dual inhibitory role—buffering AR and GR through chromatin reservoirs and the corepressor TLE3—so that FOXA1 loss can release receptors to bind chromatin more broadly (PMID:24875621, PMID:38015476). FOXA1 also directly represses transcription of genes including TGFB3, IL-8, HIF1A, and MND1, restraining EMT, neuroendocrine differentiation, hypoxia programs, and invasion when present, and it suppresses interferon signaling by binding and inhibiting the STAT2 DNA-binding domain independently of its own transactivation (PMID:30511964, PMID:28319070, PMID:35931888, PMID:34101624). FOXA1 chromatin occupancy and stability are tuned by an extensive post-translational code: LSD1 demethylates K270 to stabilize binding while SETD7 methylates the same residue to disrupt it, EZH2-mediated K295 methylation is read by BUB3 to recruit USP7 and stabilize the protein, SUMOylation and O-GlcNAcylation reshape mobility and cistrome, and the E3 ligases NEDD4 and ZFP91 target it for degradation (PMID:32868907, PMID:37549269, PMID:33827814, PMID:25127374, PMID:37595040, PMID:33530829, PMID:31046116). FOXA1 further couples transcription to epigenome remodeling by recruiting DNA polymerase β to drive lineage-specific DNA demethylation and by forming a feed-forward loop with TET1 to maintain enhancer hypomethylation (PMID:27500525, PMID:27257062). Cancer-associated mutations partition into mechanistically distinct classes that enhance chromatin mobility, increase DNA affinity, or relax DNA-motif preference to activate alternative cistromes and drive luminal, neuroendocrine, metastatic, or WNT-driven programs (PMID:31243372, PMID:31243370, PMID:32888433).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2005 High

    Established that FOXA1 acts in tissue morphogenesis and engages steroid receptors directly, framing it as both a developmental regulator and a receptor partner.

    Evidence Foxa1/Foxa2 double-knockout mice for lung branching plus GST pull-down with the AR DNA-binding domain

    PMID:15668254 PMID:16467259

    Open questions at the time
    • Mechanism of chromatin opening not yet addressed
    • AR interaction shown only by pull-down/EMSA in a single lab
  2. 2010 High

    Defined FOXA1 as the pioneer factor that dictates genome-wide ER binding and is essential for ERα expression and hormone-driven mammary morphogenesis, anchoring its role in hormone-responsive epithelia.

    Evidence ChIP-seq with siRNA knockdown in breast cancer cells and Foxa1-null mouse mammary phenotyping

    PMID:20501593 PMID:21151129

    Open questions at the time
    • Biophysical basis of chromatin opening unresolved
    • Did not address regulation of FOXA1 itself
  3. 2014 High

    Revealed FOXA1 as a quantitative, dual regulator of AR—opening chromatin to recruit AR to low-affinity sites while also sequestering AR in reservoirs—rather than a simple positive pioneer.

    Evidence ChIP-seq with FOXA1 titration, knockdown, and overexpression in prostate cancer cells

    PMID:24875621

    Open questions at the time
    • Did not define the corepressor mediating sequestration
    • Equilibrium parameters not measured biochemically
  4. 2016 High

    Connected FOXA1 transcriptional pioneering to active DNA-demethylation, showing it shapes the lineage epigenome through POLB recruitment and a TET1 feed-forward loop.

    Evidence Reciprocal Co-IP, genome-wide methylome, POLB ChIP-seq, and TET1 depletion experiments

    PMID:27257062 PMID:27500525

    Open questions at the time
    • Direct enzymatic coupling of FOXA1 to demethylation machinery not reconstituted
    • Generality across non-breast lineages untested
  5. 2019 High

    Resolved the functional consequences of cancer mutations into structurally distinct classes that alter chromatin mobility, DNA affinity, or motif preference, explaining how FOXA1 alterations drive divergent oncogenic programs.

    Evidence Large cohort genomics with functional cell assays, organoid proliferation, ATAC-seq, and motif mutagenesis

    PMID:31243370 PMID:31243372

    Open questions at the time
    • Structural details of altered DNA-binding inferred, not crystallographically resolved
    • In vivo tumor initiation by each class incompletely tested
  6. 2020 High

    Identified K270 methylation status as a switch controlling FOXA1 chromatin binding, with LSD1 demethylation stabilizing occupancy.

    Evidence Co-IP, in vitro demethylation assays, K270 mutagenesis, ChIP-seq, and xenografts

    PMID:32868907

    Open questions at the time
    • Opposing writer not yet identified at this stage
    • Stoichiometry of modification in vivo unknown
  7. 2021 High

    Expanded the PTM code by defining EZH2→BUB3→USP7 K295 methyl-stabilization and a STAT2-binding immune-suppressive activity, plus NEDD4 ubiquitination, distinguishing FOXA1 stability and non-genomic functions.

    Evidence In vitro methylation/ubiquitination assays, Co-IP for STAT2 and NEDD4, ChIP, and in vivo models

    PMID:33530829 PMID:33827814 PMID:34101624

    Open questions at the time
    • Interplay between competing PTMs not integrated
    • STAT2 suppression structural interface not mapped
  8. 2023 High

    Defined SETD7 as the K270 methyltransferase opposing LSD1 and established O-GlcNAcylation as a cistrome-switching modification recruiting MeCP2, completing a writer/eraser logic for FOXA1 regulation.

    Evidence In vitro methyltransferase assays, site-specific PTM mutagenesis, Co-IP, ChIP-seq, ATAC-seq, and metastasis models

    PMID:37549269 PMID:37595040

    Open questions at the time
    • Combinatorial effect of K270 methylation and O-GlcNAcylation untested
    • Upstream signals controlling these enzymes in vivo unclear
  9. 2023 High

    Provided a biophysical basis for pioneering by showing FOXA1 IDRs form condensates that dissolve condensed chromatin.

    Evidence Live-cell imaging, FRAP, condensate dissolution assays, ATAC-seq, and IDR deletion mutagenesis

    PMID:38101414

    Open questions at the time
    • Composition of FOXA1 condensates in vivo not defined
    • Link between condensates and specific PTMs unexplored
  10. 2024 High

    Demonstrated druggability and cofactor dependence of the FOXA1 cistrome through covalent C258 ligands that relax DNA preference and NSD2-dependent H3K36 methylation that sustains FOXA1:AR enhancers.

    Evidence Chemical proteomics, ChIP-seq, ATAC-seq, NSD2 genetic inactivation, and PROTAC degraders in prostate cancer models

    PMID:39251788 PMID:39413792

    Open questions at the time
    • Therapeutic window of covalent ligands not established
    • How NSD2 is recruited specifically to FOXA1:AR sites unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the full set of competing PTMs, condensate dynamics, and cofactor circuits are integrated to determine FOXA1's tissue- and context-specific cistrome remains unresolved.
  • No unified quantitative model linking PTM state to chromatin output
  • Structural mechanism of mutant motif relaxation not solved
  • In vivo interplay of activator vs repressor roles per tissue undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
ARESR1EZH2LSD1NSD2STAT2TET1TLE3

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 FOXA1 acts as a pioneer factor that determines genome-wide ER chromatin binding and gene expression; almost all ER-chromatin interactions depended on FOXA1 presence, and FOXA1 influenced genome-wide chromatin accessibility. CTCF was identified as an upstream negative regulator of FOXA1-chromatin interactions. ChIP-seq, siRNA knockdown, chromatin accessibility assays in breast cancer cells Nature genetics High 21151129
2019 Class-1 FOXA1 wing-2 domain mutations enhance chromatin mobility and binding frequency, strongly transactivating a luminal androgen-receptor program. Class-2 C-terminal truncation mutations increase DNA affinity enabling dominant chromatin binding and promote WNT pathway-driven metastasis through TLE3 inactivation. Class-3 rearrangements reposition a regulatory element (FOXMIND) to drive FOXA1 overexpression. Aggregate cohort genomic analysis, functional cell-based assays, structural classification of mutations Nature High 31243372
2019 Wing-2 FOXA1 mutations confer gain-of-function with exaggerated pro-luminal differentiation; R219 mutations block luminal differentiation and activate a neuroendocrine/mesenchymal program by altering DNA-binding preference from canonical (GTAAAC/T) to a non-canonical motif (GTAAAG/A), as shown by ATAC-seq and reporter assays. Mouse prostate organoid proliferation assays, ATAC-seq, reporter assays, mutagenesis of 14 FOXA1 variants Nature High 31243370
2020 LSD1 (KDM1A) associates with FOXA1 and promotes FOXA1 chromatin binding by demethylating FOXA1 at lysine-270, adjacent to the wing-2 region of the forkhead DNA-binding domain. LSD1 inhibition globally disrupts FOXA1 chromatin binding and downstream androgen-receptor binding. Co-IP, ChIP-seq, in vitro demethylation assays, site-directed mutagenesis of K270, in vivo xenograft models Nature genetics High 32868907
2021 EZH2 methylates FOXA1 at lysine-295; this methylation is recognized by BUB3, which recruits USP7 deubiquitinase to remove ubiquitination and stabilize FOXA1 protein. This PTM cascade promotes prostate cancer growth and cell cycle gene regulation. In vitro methylation assays, Co-IP, ubiquitination assays, siRNA knockdown, xenograft tumor models Science advances High 33827814
2023 SETD7 is the methyltransferase responsible for methylating FOXA1 at K270, counteracting LSD1-mediated demethylation; SETD7-mediated K270 methylation disrupts FOXA1 chromatin binding and transcriptional activity, and SETD7 acts as a tumor suppressor in prostate cancer. In vitro methyltransferase assay, ChIP-seq, knockdown/overexpression experiments, prostate cancer cell and in vivo models Proceedings of the National Academy of Sciences of the United States of America High 37549269
2016 FOXA1 associates with DNA repair complexes and is required for genomic targeting of DNA polymerase β (POLB). FOXA1-mediated recruitment of POLB drives lineage-specific DNA demethylation at FOXA1-bound regions, and this demethylation is tightly coupled to ER genomic targeting and estrogen responsiveness. Co-IP, genome-wide DNA methylome, POLB ChIP-seq, FOXA1 depletion with rescue, overexpression studies Nature genetics High 27500525
2016 FOXA1 induces TET1 expression by direct binding to TET1 cis-regulatory elements and physically interacts with TET1 protein through its CXXC domain, forming a feed-forward loop that maintains DNA hypomethylation and H3K4 methylation at lineage-specific enhancers to potentiate FOXA1 chromatin recruitment. ChIP-seq, Co-IP, TET1 depletion, genome-wide methylation analysis, reporter assays Nucleic acids research High 27257062
2014 FOXA1 is not required for AR direct chromatin binding at high-affinity AREs, but recruits AR to low-affinity half-AREs by opening chromatin around adjacent FKHD sites. Excess FOXA1 creates chromatin reservoirs retaining AR via half-AREs; FOXA1 downregulation releases AR to broadly bind AREs genome-wide even without androgen, revealing a dual pioneer and AR-inhibitory role. ChIP-seq, siRNA knockdown/overexpression, FOXA1 titration experiments in prostate cancer cells Nature communications High 24875621
2012 FoxA1 depletion causes significant redistribution of both androgen receptor (AR) and glucocorticoid receptor (GR) cistromes in a cell-type- and receptor-specific manner, demonstrating a function for FoxA1 beyond pioneer activity in specifying cell-type specificity of steroid receptor binding. ChIP-seq after FOXA1 depletion, gene expression profiling in LNCaP-1F5 and VCaP cells Cancer research High 23269278
2010 FOXA1 is essential for ERα expression in mammary gland; Foxa1-null mice show loss of ERα expression and failure of hormone-induced ductal morphogenesis with absent terminal end buds, while GATA3 expression is maintained. In breast cancer cell lines, FOXA1 directly regulates ERα expression. Foxa1 knockout mouse model, mammary gland phenotyping, breast cancer cell line knockdown, RT-PCR and immunostaining Development (Cambridge, England) High 20501593
2005 Foxa1 and Foxa2 together are required for lung branching morphogenesis; double-knockout inhibits cell proliferation, epithelial differentiation, and branching with loss of Shh signaling. Foxa1 and Foxa2 regulate Shh and Shh-dependent genes in respiratory epithelial cells. Conditional double-knockout mouse models (Foxa2Δ/Δ;Foxa1-/-), gene expression analysis, histology The Journal of biological chemistry High 15668254
2021 In NEPC, FOXA1 is reprogrammed from androgen-receptor-associated to neuroendocrine-specific regulatory elements. NEPC requires FOXA1 for proliferation and NE lineage gene expression. Ectopic expression of ASCL1 and NKX2-1 in prostate adenocarcinoma cells is sufficient to reprogram FOXA1 binding to NE regulatory elements and induce enhancer activity. ChIP-seq (histone modifications), FOXA1 knockdown, ectopic TF expression, patient-derived xenografts Nature communications High 33785741
2018 FOXA1 directly occupies an upstream enhancer of TGFB3 to inhibit its transcription; FOXA1 loss upregulates TGFβ3, which activates TGF-β signaling, EMT, and cell motility. Pharmacological TGF-β receptor I inhibition blocks FOXA1 loss-induced invasion. ChIP assay, siRNA knockdown, SMAD2 phosphorylation measurement, tissue microarray, xenograft invasion assays The Journal of clinical investigation High 30511964
2017 FOXA1 directly binds the promoter of IL-8 to inhibit its expression; FOXA1 loss induces IL-8, which activates MAPK/ERK pathway (ERK phosphorylation) and ENO2 expression, driving neuroendocrine differentiation. IL-8 knockdown or ERK inhibition abolishes FOXA1 loss-induced NE differentiation. ChIP assay, siRNA knockdown, ERK phosphorylation assay, IL-8 blockade, xenograft models Oncogene High 28319070
2022 FOXA1 directly binds an intragenic enhancer of HIF1A to inhibit its expression; FOXA1 downregulation induces hypoxia transcriptional programs via HIF1A, which upregulates CCL2 to promote immunosuppressive macrophage infiltration and cancer cell invasion. ChIP assay, siRNA knockdown, HIF1A pharmacological inhibition, macrophage infiltration assays, xenograft invasion studies Oncogene High 35931888
2021 FOXA1 binds the STAT2 DNA-binding domain and suppresses STAT2 DNA-binding activity and IFN signaling gene expression, suppressing cancer immune response independently of FOXA1 transactivation activity and independently of FOXA1 cancer mutations. Co-IP, ChIP, siRNA knockdown, IFN signaling gene expression assays in prostate and breast cancer cells and mouse models The Journal of clinical investigation High 34101624
2023 FOXA1 forms submicron condensates through N- and C-terminal intrinsically disordered regions (IDRs); these IDRs enable FOXA1 to dissolve condensed chromatin. DNA-binding capacity contributes to both condensate formation and condensed-chromatin dissolution. IDR-mediated condensate formation governs FOXA1 binding to condensed chromatin to regulate proliferation and migration. Live-cell imaging, FRAP, condensate dissolution assays, genome-wide ATAC-seq, IDR deletion mutagenesis Molecular cell High 38101414
2024 Covalent small molecules react with FOXA1 at C258 within the forkhead DNA-binding domain in a DNA-dependent manner, redistributing FOXA1 genome-wide binding and altering chromatin accessibility. Motif analysis indicates ligands relax canonical DNA-binding preference by strengthening interactions with suboptimal sequences near C258. Chemical proteomics, ChIP-seq, ATAC-seq, covalent ligand competition assays Molecular cell High 39413792
2005 Both Foxa1 and Foxa2 physically interact with the DNA-binding domain of AR via GST pull-down; this interaction enables Foxa proteins to be recruited to AR binding sites without a Foxa binding site, and AR can be recruited to Foxa binding sites without an AR binding site. Foxa1 regulates prostate-specific genes (PSA, probasin) while Foxa2 regulates epididymis-specific genes (mE-RABP). GST pull-down, gel-shift (EMSA), ChIP, transient transfection reporter assays Annals of the New York Academy of Sciences Medium 16467259
2006 FOXA1 binds a specific site in the p27(Kip1) promoter (within the BRCA1-responsive element) to activate p27 transcription. BRCA1 co-expression synergistically activates the p27 promoter and increases FOXA1 protein half-life. Mutation of the FOXA1 binding site abrogates both FOXA1 and BRCA1-mediated activation. EMSA with supershift, transient transfection reporter assays, mutagenesis, half-life analysis, siRNA knockdown of BRCA1 Oncogene Medium 16331276
2014 FOXA1 SUMOylation occurs at K6, K389, and K267 (proximal to the DNA-binding domain). Mutation of SUMO sites slows FOXA1 nuclear mobility (FRAP) and further retards AR mobility, enhances FOXA1 chromatin occupancy at the PSA locus, increases FOXA1 transcriptional activity with AR, and alters LNCaP cell proliferation. SUMOylation assays in COS-1 cells, FRAP in HEK293 cells, ChIP, gene expression assays in LNCaP cells Molecular endocrinology (Baltimore, Md.) Medium 25127374
2018 A compact palindromic DNA element (DIV) induces FOXA1 homodimerization with strongly positive cooperativity, strictly constrained by precise half-site spacing. FOXA1-dependent transcriptional activity declines when homodimeric binding is disrupted, and DIV sites show increased accessibility in response to PI3K inhibition. ChIP-seq reanalysis, EMSA cooperativity assays, reporter gene assays, structural modeling Nucleic acids research Medium 29669022
2020 Wing-2 FOXA1 mutations in breast cancer display increased chromatin binding at ER loci upon estrogen stimulation and enhanced ER-mediated transcription without changes in chromatin accessibility. The breast cancer-specific SY242CS mutation opens distinct chromatin regions and activates an alternative cistrome through a conformational change enabling stable binding to a non-canonical DNA motif. ChIP-seq, ATAC-seq, structural modeling, breast cancer patient cohort analysis Cancer cell High 32888433
2014 FOXA1 directly inhibits EZH2 histone methyltransferase activity through its C-terminal histone-binding motif, opposing EZH2-mediated CDKN2A repression. Loss of FOXA1 is required, in addition to EZH2 overexpression, to bypass RAS-induced senescence via CDKN2A silencing. In vitro HMTase assay, epistasis experiments (siRNA double knockdown), oncogenic transformation assays in prostate and breast cancer cells Biochemical and biophysical research communications Medium 25264199
2009 Foxa1 and Foxa2 are essential for differentiation of intestinal goblet cells (via Muc2 regulation) and enteroendocrine L- and D-cells (glucagon-like peptide, somatostatin, peptide YY); double intestinal-specific knockout reduces expression of Islet-1 and Pax6, placing Foxa1/2 upstream of a broader enteroendocrine transcription factor network. Villin-Cre conditional double-knockout mice, immunohistochemistry, RT-PCR, mRNA quantification Gastroenterology High 19737569
2010 Foxa1 and Foxa2 together control expression of ChREBP (Mlxipl) directly in beta cells; combined inactivation causes impaired glucose-stimulated insulin secretion and calcium oscillations more severe than Foxa2 alone, and elevates neural differentiation genes, demonstrating redundant and distinct roles in maintaining beta-cell metabolic and secretory identity. Inducible conditional double-knockout mice, glucose tolerance tests, calcium imaging, RNA expression profiling Molecular endocrinology (Baltimore, Md.) High 20534694
2010 Foxa2 directly binds Gli2 genomic regulatory regions (confirmed by ChIP) and, together with Foxa1, attenuates Shh signaling by inhibiting Gli2 transcription in ventral midbrain progenitors. Loss/gain-of-function studies show Foxa1 and Foxa2 positively regulate Shh expression while also negatively regulating its downstream transducer Gli2. ChIP, conditional Wnt1-Cre;Foxa2flox/flox knockout, gain-of-function in mice Mechanisms of development Medium 21093585
2021 NEDD4 physically interacts with FOXA1 (Co-IP) and triggers its ubiquitination and proteasomal degradation. FOXA1 transcriptionally activates miR-340-5p, which binds ATF1 mRNA. NEDD4-mediated FOXA1 destabilization thus suppresses miR-340-5p and elevates ATF1 to promote colon cancer progression. Co-IP, ubiquitination assay, ChIP, luciferase reporter assay, siRNA experiments in colon cancer cells RNA biology Medium 33530829
2020 ZFP91 ubiquitinates FOXA1 and promotes its degradation; ZFP91 knockdown reduces FOXA1 polyubiquitination, increases FOXA1 protein stability, and sensitizes gastric cancer cells to chemotherapy. Co-IP, ubiquitination assay, ZFP91 siRNA knockdown, protein stability measurement Carcinogenesis Medium 31046116
2015 Nuclear receptor SHP inhibits FOXA1-mediated transcriptional activation of Bhmt (betaine-homocysteine methyltransferase) and cystathionine γ-lyase, controlling oscillatory homocysteine metabolism in mice. ChIP, RNA-seq, metabolomics in SHP-null mice, dietary manipulation experiments Gastroenterology Medium 25701738
2014 FOXA1 interacts with AR (Co-IP) in endometrial cancer cells and both bind directly to the MYC promoter and enhancer (ChIP). FOXA1 promotes AR-mediated transcription of XBP1, MYC, ZBTB16, and UHRF1, activating Notch1/Hes1 expression in an AR-dependent manner to promote cancer cell proliferation. Co-IP, ChIP-PCR, siRNA/shRNA knockdown, transfection reporter assays, xenograft tumor formation BMC cancer Medium 24512546
2016 Twist1 represses FOXA1 expression by binding the FOXA1 proximal promoter and recruiting the NuRD transcriptional repressor complex to de-acetylate H3K9 and inhibit RNA polymerase II recruitment, and by blocking AP-1 recruitment. Restored FOXA1 expression in Twist1-expressing cells reduces integrin α5, integrin β1 and MMP9 and inhibits invasion/metastasis. ChIP, promoter reporter assays, Co-IP (NuRD recruitment), siRNA/overexpression, xenograft metastasis models Oncogene Medium 27524420
2008 PPARγ activation induces FOXA1 expression as an intermediary transcription factor; FOXA1 (and IRF-1) bind UPK1a, UPK2, and UPK3a promoters (confirmed by EMSA) and their siRNA knockdown abrogates PPARγ-induced uroplakin expression, placing FOXA1 downstream of PPARγ in a urothelial differentiation program. Microarray, EMSA, siRNA knockdown, gene expression analysis in primary normal human urothelial cells Cell death and differentiation Medium 18688264
2022 FOXA1 directly binds regulatory regions of splicing-related genes including HNRNPK and SRSF1, controlling their expression and thereby orchestrating alternative splicing dysregulation across prostate cancer transcriptomes through an 'exon definition' mechanism that reduces NMD-targeted isoforms. ChIP-seq, transcriptome analysis of 500 prostate cancer samples, siRNA knockdown, functional cell proliferation assays Cell reports Medium 36170835
2023 O-GlcNAcylation of FOXA1 at Thr432, Ser441, and Ser443 regulates FOXA1 protein stability and chromatin assembly. O-GlcNAcylation triggers recruitment of the transcriptional repressor MeCP2 to FOXA1, switching FOXA1 chromatin-binding sites to adhesion-related gene loci (EPB41L3, COL9A2) to promote breast cancer metastasis. Site-specific mutagenesis, Co-IP, ChIP-seq, ATAC-seq, in vitro and in vivo metastasis assays Science advances High 37595040
2022 CREB5 physically interacts with FOXA1 and AR at transcription regulatory elements active in mCRPC, reprogramming FOXA1 nuclear protein-protein interaction network in response to enzalutamide. CREB5/FOXA1 co-interacting factors TBX3 and NFIC regulate cell viability and ART resistance. ChIP-seq, rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME), Co-IP, patient transcriptome analysis eLife Medium 35550030
2024 NSD2 associates with FOXA1 at tumor-specific AR enhancers containing the chimeric FOXA1:AR half-motif; NSD2 inactivation disrupts >65% of the AR cistrome and impairs AR transactivation. NSD2 H3K36 dimethyltransferase activity is required for these AR/FOXA1-dependent enhancer circuitries. ChIP-seq, NSD2 inactivation, FOXA1 ChIP, motif analysis, PROTAC degrader studies in prostate cancer models Nature genetics High 39251788
2024 FOXA1-mediated repression of GR (NR3C1) occurs via the corepressor TLE3; FOXA1 silencing potentiates GR chromatin binding and transcriptional activity rather than restricting it. Pre-accessible chromatin sites with FOXA1 occupancy are the exclusive sites of AR-to-GR replacement under enzalutamide treatment. Genome-wide ChIP-seq, ATAC-seq, FOXA1 siRNA silencing, TLE3 Co-IP/ChIP in prostate cancer cells Nucleic acids research High 38015476
2017 FOXA1 transcriptionally activates the PLOD2 promoter by directly binding it; this occurs downstream of a PI3K/AKT signaling axis (EGFR-PI3K/AKT-FOXA1-PLOD2), and elevated PLOD2 promotes NSCLC metastasis by enhancing migration and collagen reorganization. ChIP assay, luciferase reporter assay, siRNA knockdown, orthotopic implantation metastasis model Cell death & disease Medium 29072684
2015 FOXA1 depletion in CRPC cells abrogates oncogenic potential of constitutively active AR variants (AR-Vs); ~41% of the AR-V transcriptome requires FOXA1, and FOXA1 depletion attenuates AR-V chromatin binding at co-regulated genes. AR-V protein levels paradoxically increase upon FOXA1 loss due to loss of negative feedback on the AR gene. FOXA1 siRNA/shRNA knockdown, gene expression profiling, AR-V ChIP, proliferation assays in CWR22Rv1 cells Oncotarget Medium 26336819
2014 Foxa1 and Foxa2 directly bind and activate promoter regions of Nkx2.2, Kir6.2, Sur1, Gipr, Isl1, and Pou3f4 genes in alpha cells. Foxa1 specifically regulates glucagon gene expression through the G2 element, while combined Foxa1/Foxa2 depletion is required to affect glucagon secretion. siRNA knockdown of Foxa1 and Foxa2 in primary rat alpha cells, ChIP, qPCR, glucagon secretion assays Endocrinology Medium 25057789
2017 Pioneer factors FOXA1 and FOXA2 are required for glucocorticoid receptor (GR) recruitment to the LEFTY1 promoter in endometrial cells; E2 antagonizes glucocorticoid-mediated LEFTY1 induction by reducing FOXA1, FOXA2, and GR recruitment. Multiple additional GR-dependent genes require FOXA1/2 for induction. ChIP showing GR and FOXA1/2 co-recruitment, siRNA knockdown of FOXA1/2, gene expression profiling in immortalized and primary human endometrial cells Endocrinology Medium 28938408
2023 FOXA1 directly binds the MND1 promoter to inhibit its transcription (ChIP and luciferase assay); MND1 interacts with TKT (Co-IP and mass spectrometry) and activates the PI3K/AKT signaling axis to promote gastric cancer progression and oxaliplatin resistance. Luciferase reporter assay, ChIP, Co-IP, mass spectrometry, siRNA knockdown, in vitro and in vivo assays Cancer cell international Medium 37817120

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nature genetics 699 21151129
2019 Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer. Nature 243 31243372
2019 FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes. Nature 224 31243370
2005 Compensatory roles of Foxa1 and Foxa2 during lung morphogenesis. The Journal of biological chemistry 224 15668254
2007 FOXA1 expression in breast cancer--correlation with luminal subtype A and survival. Clinical cancer research : an official journal of the American Association for Cancer Research 207 17671124
2010 FOXA1 is an essential determinant of ERalpha expression and mammary ductal morphogenesis. Development (Cambridge, England) 202 20501593
2012 FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer research 191 23269278
2004 Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues. Gene expression patterns : GEP 186 15567715
2012 FOXA1: a transcription factor with parallel functions in development and cancer. Bioscience reports 178 22115363
2014 Cooperativity and equilibrium with FOXA1 define the androgen receptor transcriptional program. Nature communications 163 24875621
2011 FOXA1: master of steroid receptor function in cancer. The EMBO journal 160 21934649
2021 Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer. Nature communications 134 33785741
2020 Pioneer of prostate cancer: past, present and the future of FOXA1. Protein & cell 132 32946061
2009 Foxa1 and Foxa2 control the differentiation of goblet and enteroendocrine L- and D-cells in mice. Gastroenterology 131 19737569
2016 Twist1 promotes breast cancer invasion and metastasis by silencing Foxa1 expression. Oncogene 130 27524420
2018 Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression. The Journal of clinical investigation 127 30511964
2017 FOXA1 inhibits prostate cancer neuroendocrine differentiation. Oncogene 122 28319070
2020 Chromatin binding of FOXA1 is promoted by LSD1-mediated demethylation in prostate cancer. Nature genetics 107 32868907
2004 About GATA3, HNF3A, and XBP1, three genes co-expressed with the oestrogen receptor-alpha gene (ESR1) in breast cancer. Molecular and cellular endocrinology 107 15149721
2020 FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer. Cancer cell 100 32888433
2010 Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature beta-cell. Molecular endocrinology (Baltimore, Md.) 98 20534694
2017 PLOD2 regulated by transcription factor FOXA1 promotes metastasis in NSCLC. Cell death & disease 82 29072684
2021 FOXA1 overexpression suppresses interferon signaling and immune response in cancer. The Journal of clinical investigation 80 34101624
2005 Foxa1 and Foxa2 interact with the androgen receptor to regulate prostate and epididymal genes differentially. Annals of the New York Academy of Sciences 80 16467259
2018 FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer. eLife 66 30475207
2006 BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27(Kip1). Oncogene 65 16331276
2015 GATA-3 and FOXA1 expression is useful to differentiate breast carcinoma from other carcinomas. Human pathology 64 26527523
2014 FOXA1 promotes tumor cell proliferation through AR involving the Notch pathway in endometrial cancer. BMC cancer 63 24512546
2021 Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer. Science advances 62 33827814
2008 FOXA1 and IRF-1 intermediary transcriptional regulators of PPARgamma-induced urothelial cytodifferentiation. Cell death and differentiation 61 18688264
2014 Modulation of androgen receptor by FOXA1 and FOXO1 factors in prostate cancer. International journal of biological sciences 60 24948874
2016 Nucleation of DNA repair factors by FOXA1 links DNA demethylation to transcriptional pioneering. Nature genetics 56 27500525
2024 FOXA1 and FOXA2: the regulatory mechanisms and therapeutic implications in cancer. Cell death discovery 55 38605023
2016 FOXA1 defines cancer cell specificity. Science advances 55 27034986
2016 FOXA1 potentiates lineage-specific enhancer activation through modulating TET1 expression and function. Nucleic acids research 55 27257062
2021 FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer. Cancers 54 34680352
2007 FOXA1 as a therapeutic target for breast cancer. Expert opinion on therapeutic targets 53 17373880
2010 Foxa1 and Foxa2 positively and negatively regulate Shh signalling to specify ventral midbrain progenitor identity. Mechanisms of development 52 21093585
2009 FOXA1 in breast cancer. Expert reviews in molecular medicine 52 19261198
2023 hsa_circ_0007919 induces LIG1 transcription by binding to FOXA1/TET1 to enhance the DNA damage response and promote gemcitabine resistance in pancreatic ductal adenocarcinoma. Molecular cancer 49 38044421
2015 Interactions Between Nuclear Receptor SHP and FOXA1 Maintain Oscillatory Homocysteine Homeostasis in Mice. Gastroenterology 48 25701738
2014 Foxa1 and Foxa2 regulate α-cell differentiation, glucagon biosynthesis, and secretion. Endocrinology 48 25057789
2023 FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer. Science advances 47 37595040
2012 Cross-regulation between FOXA1 and ErbB2 signaling in estrogen receptor-negative breast cancer. Neoplasia (New York, N.Y.) 46 22577344
2013 FOXA1 mutations in hormone-dependent cancers. Frontiers in oncology 45 23420418
2023 FOXA1 forms biomolecular condensates that unpack condensed chromatin to function as a pioneer factor. Molecular cell 44 38101414
2022 FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma. Developmental cell 43 35835117
2015 FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer. Oncotarget 38 26336819
2022 FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation. Nature communications 37 36323682
2023 Celastrol inhibits gastric cancer cell proliferation, migration, and invasion via the FOXA1/CLDN4 axis. Toxicology research 33 37397926
2024 Redirecting the pioneering function of FOXA1 with covalent small molecules. Molecular cell 31 39413792
2022 FOXA1 regulates alternative splicing in prostate cancer. Cell reports 31 36170835
2021 NEDD4 triggers FOXA1 ubiquitination and promotes colon cancer progression under microRNA-340-5p suppression and ATF1 upregulation. RNA biology 31 33530829
2014 Nuclear mobility and activity of FOXA1 with androgen receptor are regulated by SUMOylation. Molecular endocrinology (Baltimore, Md.) 31 25127374
2021 The estrogen receptor/GATA3/FOXA1 transcriptional network: lessons learned from breast cancer. Current opinion in structural biology 29 34225008
2019 Dysregulation of miR-431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28 30624964
2018 miR-132 Targets FOXA1 and Exerts Tumor-Suppressing Functions in Thyroid Cancer. Oncology research 28 29523221
2024 NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis. Nature genetics 27 39251788
2019 Hypermethylation of FOXA1 and allelic loss of PTEN drive squamous differentiation and promote heterogeneity in bladder cancer. Oncogene 27 31636388
2021 Genetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility. Nature communications 26 34518541
2021 MicroRNA-100 inhibits breast cancer cell proliferation, invasion and migration by targeting FOXA1. Oncology letters 26 34671430
2018 Frequent mutation of the FOXA1 untranslated region in prostate cancer. Communications biology 26 30272002
2022 CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies. eLife 25 35550030
2017 Role of transcription factor FOXA1 in non‑small cell lung cancer. Molecular medicine reports 25 29115441
2014 FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis. Biochemical and biophysical research communications 24 25264199
2023 FOXA1 in prostate cancer. Asian journal of andrology 23 36018068
2014 MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer. Oncotarget 23 25071007
2014 Switch in FOXA1 status associates with endometrial cancer progression. PloS one 22 24849812
2021 FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036. NPJ breast cancer 21 33980863
2020 FOXA1 Promotes Cell Proliferation and Suppresses Apoptosis in HCC by Directly Regulating miR-212-3p/FOXA1/AGR2 Signaling Pathway. OncoTargets and therapy 21 32606743
2017 Overexpression of FOXA1 inhibits cell proliferation and EMT of human gastric cancer AGS cells. Gene 21 29129808
2020 Frequent FOXA1-Activating Mutations in Extramammary Paget's Disease. Cancers 19 32235312
2018 Transcriptome analyses reveal FOXA1 dysregulation in mammary and extramammary Paget's disease. Human pathology 19 29630912
2016 Foxa1 gene and protein in developing rat eccrine sweat glands. Journal of molecular histology 19 27787633
2021 FOXA1 promotes prostate cancer angiogenesis by inducing multiple pro-angiogenic factors expression. Journal of cancer research and clinical oncology 18 34258652
2018 DNA-mediated dimerization on a compact sequence signature controls enhancer engagement and regulation by FOXA1. Nucleic acids research 18 29669022
2024 Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer. Nucleic acids research 17 38015476
2023 SETD7 functions as a transcription repressor in prostate cancer via methylating FOXA1. Proceedings of the National Academy of Sciences of the United States of America 17 37549269
2022 FOXA1 inhibits hypoxia programs through transcriptional repression of HIF1A. Oncogene 17 35931888
2022 Integrated analysis reveals FOXA1 and Ku70/Ku80 as targets of ivermectin in prostate cancer. Cell death & disease 17 36050295
2021 The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection. Development (Cambridge, England) 17 34323272
2020 FOXA1-induced circOSBPL10 potentiates cervical cancer cell proliferation and migration through miR-1179/UBE2Q1 axis. Cancer cell international 17 32831649
2016 FOXA1 expression affects the proliferation activity of luminal breast cancer stem cell populations. Cancer science 17 26708273
2022 FOXA1 can be modulated by HDAC3 in the progression of epithelial ovarian carcinoma. Journal of translational medicine 16 34991620
2020 The ubiquitinase ZFP91 promotes tumor cell survival and confers chemoresistance through FOXA1 destabilization. Carcinogenesis 16 31046116
2020 FOXA1-induced LINC01207 facilitates head and neck squamous cell carcinoma via up-regulation of TNRC6B. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 16 32450521
2019 Association of FOXA1 and EMT markers (Twist1 and E-cadherin) in breast cancer. Molecular biology reports 16 30941644
2023 FOXA1 prolongs S phase and promotes cancer progression in non-small cell lung cancer through upregulation of CDC5L and activation of the ERK1/2 and JAK2 pathways. The Kaohsiung journal of medical sciences 15 37658700
2018 Silencing FOXA1 gene regulates liver cancer cell apoptosis and cell proliferation. European review for medical and pharmacological sciences 15 29424896
2023 FOXA1/MND1/TKT axis regulates gastric cancer progression and oxaliplatin sensitivity via PI3K/AKT signaling pathway. Cancer cell international 14 37817120
2018 Foxa1 and Foxa2 in thymic epithelial cells (TEC) regulate medullary TEC and regulatory T-cell maturation. Journal of autoimmunity 14 30061015
2017 Pioneer Factors FOXA1 and FOXA2 Assist Selective Glucocorticoid Receptor Signaling in Human Endometrial Cells. Endocrinology 14 28938408
2022 A Transcriptional Link between HER2, JAM-A and FOXA1 in Breast Cancer. Cells 13 35203384
2020 IGF-1 and hyperglycaemia-induced FOXA1 and IGFBP-2 affect epithelial to mesenchymal transition in prostate epithelial cells. Oncotarget 13 32655839
2020 FOXA1 Expression in Nasopharyngeal Carcinoma: Association with Clinicopathological Characteristics and EMT Markers. BioMed research international 13 32685483
2019 Androgen receptor and FOXA1 coexpression define a "luminal-AR" subtype of feline mammary carcinomas, spontaneous models of breast cancer. BMC cancer 13 31888566
2017 FOXA1 is expressed in ovarian mucinous neoplasms. Pathology 13 28238418
2024 FOXA1/UBE2T Inhibits CD8+T Cell Activity by Inducing Mediates Glycolysis in Lung Adenocarcinoma. Frontiers in bioscience (Landmark edition) 12 38682180
2024 TGF-β1 facilitates gallbladder carcinoma metastasis by regulating FOXA1 translation efficiency through m6A modification. Cell death & disease 12 38886389
2019 SOX9 dependent FOXA1 expression promotes tumorigenesis in lung carcinoma. Biochemical and biophysical research communications 12 31221478

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