Affinage

FHIT

Bis(5'-adenosyl)-triphosphatase · UniProt P49789

Length
147 aa
Mass
16.9 kDa
Annotated
2026-04-28
100 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FHIT is a tumor suppressor diadenosine polyphosphate hydrolase that maintains genome stability and modulates apoptosis through mechanisms largely independent of its catalytic activity but dependent on substrate binding and the Src-phosphorylated residue Y114 (PMID:9391102, PMID:15007172, PMID:16407838). FHIT preserves replication fork integrity by regulating Thymidine kinase 1 expression and nucleotide pool balance; its loss causes replication stress-induced DNA double-strand breaks that serve as substrates for APOBEC3B mutagenesis, initiating a genome-wide mutator phenotype (PMID:23209436, PMID:25401976). FHIT also partially localizes to mitochondria, where it interacts with Hsp60/Hsp10 and ferredoxin reductase to enhance mitochondrial calcium uptake and ROS-mediated apoptosis, and it directly binds β-catenin at Wnt target gene promoters to repress transcription of cyclin D1 and survivin (PMID:19622739, PMID:19004824, PMID:18077326). Additionally, FHIT suppresses epithelial-mesenchymal transition through upregulation of miR-30c and modulates the Chk1-dependent DNA damage checkpoint (PMID:25340791, PMID:23102829).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Establishing that FHIT is a diadenosine triphosphate hydrolase whose tumor suppression is catalytically independent resolved the paradox of how a metabolic enzyme could function as a tumor suppressor.

    Evidence In vitro enzymatic assay with active-site mutagenesis; hydrolase-dead mutants still suppressed tumorigenicity in nude mice

    PMID:9391102

    Open questions at the time
    • The substrate-binding vs. catalytic distinction was not yet mapped to specific residues beyond the catalytic histidine
    • The downstream effector pathway for tumor suppression was unknown
  2. 1998 High

    Discovery that Drosophila and C. elegans encode FHIT fused with a nitrilase domain (NitFhit) established evolutionary conservation and suggested functional collaboration with NIT1 in mammals.

    Evidence Cloning and enzymatic assay of Drosophila NitFhit fusion protein

    PMID:9671749

    Open questions at the time
    • The shared biochemical pathway between FHIT and NIT1 in mammals was not identified
    • Whether the fusion architecture reflects obligate functional coupling was unclear
  3. 2004 High

    Identification of Y114 as a Src phosphorylation site provided the first post-translational regulatory mechanism for FHIT and a critical residue for subsequent functional dissection.

    Evidence In vitro kinase assay and in vivo phosphorylation studies

    PMID:15007172

    Open questions at the time
    • Functional consequence of Y114 phosphorylation on tumor suppression was not yet tested
    • Whether Src-mediated phosphorylation activates or inhibits FHIT was unresolved
  4. 2006 High

    Demonstration that Y114 is required for caspase-dependent apoptosis and Akt/survivin pathway inhibition linked Src phosphorylation to a defined tumor-suppressive signaling axis, and that FHIT modulates the Hus1/Chk1 DNA damage checkpoint.

    Evidence Y114 mutant vs. wild-type adenoviral expression in lung cancer cells with apoptosis, Akt activity, and checkpoint protein readouts

    PMID:16407838 PMID:17145874

    Open questions at the time
    • Whether Akt inhibition is direct or indirect was not resolved
    • Relationship between checkpoint modulation and apoptosis induction was unclear
  5. 2007 High

    Discovery that FHIT directly binds β-catenin and represses Wnt target gene transcription independently of catalytic activity revealed a nuclear transcriptional repressor function distinct from its metabolic role.

    Evidence Co-IP, ChIP at Wnt target promoters, knockdown, enzymatic-dead mutant analysis

    PMID:18077326

    Open questions at the time
    • Mechanism of transcriptional repression (co-repressor recruitment, chromatin remodeling) was not defined
    • Whether FHIT enters the nucleus or acts at the cytoplasmic level on β-catenin was not fully clarified
  6. 2008 High

    Identification of Hsp60/Hsp10 and ferredoxin reductase as mitochondrial FHIT-interacting partners, requiring substrate-binding and Y114, established a mitochondrial axis for FHIT's proapoptotic function through ROS generation.

    Evidence Chemical cross-linking, immunoprecipitation, subcellular fractionation, ROS measurement with mutant panel

    PMID:19004824 PMID:19486340

    Open questions at the time
    • How FHIT is imported into mitochondria without a canonical transit peptide was unknown
    • Whether Fdxr stabilization is sufficient for ROS-mediated apoptosis independently of other FHIT functions was unclear
  7. 2009 High

    Demonstrating that mitochondrial FHIT enhances calcium uptake and sensitizes cells to apoptosis — while a fully mitochondrial chimera loses cell-cycle effects — separated FHIT's mitochondrial proapoptotic function from its cytoplasmic/nuclear roles.

    Evidence Live Ca2+ imaging in intact and permeabilized cells, chimeric mitochondrial-targeted FHIT

    PMID:19622739

    Open questions at the time
    • The calcium channel or transporter modulated by FHIT was not identified
    • Quantitative contribution of mitochondrial vs. non-mitochondrial FHIT to tumor suppression in vivo was undefined
  8. 2009 Medium

    Double-knockout mouse studies showing additive tumor susceptibility of Fhit and Nit1 loss established that these evolutionarily linked genes act through distinct tumor-suppressive pathways in mammals.

    Evidence Fhit−/−Nit1−/− double-knockout mouse tumorigenesis assay with subcellular localization

    PMID:19479888

    Open questions at the time
    • The Nit1-specific pathway was not defined
    • Whether cytoplasmic vs. mitochondrial co-localization mediates any residual functional overlap was not tested
  9. 2012 High

    Discovery that FHIT loss causes replication fork collapse through TK1 downregulation and nucleotide imbalance provided the first genome-instability mechanism for FHIT tumor suppression, explaining how early FHIT loss drives a mutator phenotype.

    Evidence DNA combing, DNA damage markers, TK1 expression, thymidine supplementation rescue, Fhit-knockout mouse validation

    PMID:23209436

    Open questions at the time
    • How FHIT regulates TK1 transcription was not established
    • Whether nucleotide imbalance fully accounts for all FHIT-dependent DNA damage was unclear
  10. 2012 Medium

    Epistasis experiments placed FHIT's DNA-damage suppression as dependent on Chk1 but independent of ATR/ATM, refining its position in the replication stress response.

    Evidence Kinase inhibitor experiments with FHIT mutants and DNA damage assays

    PMID:23102829

    Open questions at the time
    • Direct physical or signaling link between FHIT and Chk1 was not shown
    • How FHIT bypasses ATR-dependent Chk1 activation was unexplained
  11. 2014 Medium

    Identification of miR-30c as a FHIT-induced microRNA that suppresses EMT genes (MTDH, HMGA2, VIM, FN1) extended FHIT's tumor-suppressive reach to metastasis and epithelial-mesenchymal transition control.

    Evidence In vivo metastasis assay, miRNA target validation, gain/loss-of-function in lung cancer cells

    PMID:25340791

    Open questions at the time
    • Mechanism by which FHIT upregulates miR-30c was not defined
    • Whether miR-30c mediates FHIT effects in non-lung tissues was untested
  12. 2015 Medium

    Linking FHIT loss-induced replication stress to APOBEC3B mutagenesis explained how early FHIT silencing amplifies the somatic mutation burden driving cancer progression.

    Evidence TCGA analysis of FHIT-low/APOBEC3B-high tumors, in vitro FHIT silencing with thymidine rescue reducing APOBEC-induced TP53 mutations

    PMID:25401976

    Open questions at the time
    • Whether APOBEC3B access to ssDNA at stalled forks is the sole mechanism was not proven
    • In vivo validation in mouse models was lacking
  13. 2017 Medium

    Ribosome profiling revealed that FHIT expression reshapes translation of hundreds of cancer-associated mRNAs, consistent with its ability to degrade m7GpppN cap dinucleotides from mRNA decay intermediates.

    Evidence Genome-wide ribosome occupancy profiling in FHIT-positive vs. FHIT-negative cells

    PMID:29282095

    Open questions at the time
    • Direct evidence that cap-dinucleotide hydrolysis by FHIT alters specific mRNA translation was not provided
    • Whether translational changes are primary or secondary to FHIT's other functions was unclear
  14. 2019 Medium

    Discovery that FHIT modifies the BMPR2 pulmonary arterial hypertension phenotype, with Fhit−/− mice developing exaggerated hypoxic pulmonary hypertension reversed by enzastaurin, extended FHIT's physiological roles beyond cancer.

    Evidence siRNA screen, Fhit-knockout mouse hypoxia model, pharmacological rescue with enzastaurin

    PMID:30107138

    Open questions at the time
    • Molecular mechanism linking FHIT to BMPR2 signaling was not defined
    • Whether replication stress or other FHIT pathways mediate the vascular phenotype was unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanism by which FHIT regulates TK1 transcription, how it is imported into mitochondria without a canonical transit peptide, and whether its translational regulatory function via cap-dinucleotide hydrolysis is physiologically significant remain open questions.
  • No transcription factor or promoter element identified for FHIT-dependent TK1 regulation
  • Mitochondrial import mechanism is undefined
  • Causal link between cap hydrolysis and translational changes is not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0016787 hydrolase activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005739 mitochondrion 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 3 R-HSA-69306 DNA Replication 2
Partners
CHEK1CTNNB1FDXRHSPD1HSPE1NIT1SRC
Complex memberships
LEF1/TCF/β-catenin complex

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Fhit protein hydrolyzes dinucleotide 5',5'''-P1,P3-triphosphate (ApppA) in vitro; mutation of the central histidine abolishes hydrolase activity. Tumor suppression activity does not require the hydrolase activity, as hydrolase-dead Fhit mutants still suppress tumorigenicity in nude mice. In vitro enzymatic assay, active-site mutagenesis, nude mouse tumorigenicity assay Proceedings of the National Academy of Sciences of the United States of America High 9391102
1998 Drosophila and C. elegans encode Fhit as a fusion protein with a nitrilase domain (NitFhit); the Drosophila fusion protein retains diadenosine triphosphate (ApppA) hydrolase activity. In mammals, FHIT and NIT1 are encoded by separate genes, suggesting they collaborate in a common biochemical pathway. Cloning, enzymatic activity assay of fusion protein, expression analysis Proceedings of the National Academy of Sciences of the United States of America High 9671749
2004 Fhit is phosphorylated on tyrosine 114 (Y114) by the Src protein kinase both in vitro and in vivo, identifying Fhit as a physiological Src substrate. In vitro kinase assay, in vivo phosphorylation studies Proceedings of the National Academy of Sciences of the United States of America High 15007172
2006 Fhit Y114 residue is essential for caspase-dependent apoptosis induction in lung cancer cells; wild-type but not Y114 mutant Fhit inhibits Akt activity and reduces survivin expression, placing Fhit upstream of the PI3K-Akt-survivin pathway. Adenoviral infection with wild-type and Y114 mutant FHIT, expression profiling, Akt activity assay, apoptosis assay Oncogene High 16407838
2007 Fhit directly binds to the C-terminal domain of β-catenin, recruits to Wnt target gene promoters (cyclin D1, axin2, MMP-14, survivin) as part of the LEF1/TCF/β-catenin complex, and represses transcription of these targets. Enzymatic activity is not required for this function. Co-IP, ChIP, knockdown experiments, soft-agar assay, enzymatic dead mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 18077326
2006 Fhit modulates the mid-S DNA damage checkpoint by regulating expression of checkpoint proteins Hus1 and Chk1; mutation of Fhit Y114 abolishes this checkpoint modulation, and re-expression induces apoptosis in cancer cells but not normal cells. Exogenous Fhit expression in cells, Western blot for checkpoint proteins, apoptosis assay, Y114 mutant analysis Cancer research Medium 17145874
2009 Fhit localizes partially to mitochondria and enhances mitochondrial calcium uptake, sensitizing cells to apoptosis. A chimeric fully mitochondrial Fhit retains Ca2+ signaling and proapoptotic properties but loses effects on cell cycle. Subcellular fractionation, live imaging of Ca2+ signaling in intact and permeabilized cells, chimeric protein expression, apoptosis assay Proceedings of the National Academy of Sciences of the United States of America High 19622739
2008 Fhit interacts with Hsp60/Hsp10 chaperone machinery and ferredoxin reductase (Fdxr); substrate-binding and Y114 phosphorylation are required for these interactions and for mitochondrial localization. Loss of these interactions reduces Fhit tumor suppressor activity and impairs oxidative stress-induced apoptosis. Chemical cross-linking, immunoprecipitation, subcellular fractionation, mutant expression, flow cytometry, ROS measurement The Journal of biological chemistry High 19004824
2009 Fhit binds and stabilizes ferredoxin reductase (Fdxr) in mitochondria; when Fdxr is overexpressed it produces reactive oxygen species (ROS) that induce apoptosis. Fhit-positive cancer cells produce higher ROS upon H2O2 exposure than Fhit-negative cells. Immunoprecipitation, ROS measurement, apoptosis assay, overexpression experiments Cancer science Medium 19486340
2012 Fhit depletion causes replication stress-induced DNA double-strand breaks and defective replication fork progression (fork stalling and collapse). The mechanism involves regulation of Thymidine kinase 1 (TK1) expression and thymidine triphosphate pool levels; restoring nucleotide balance rescues replication defects and suppresses DNA breakage in Fhit-deficient cells. DNA combing, DNA damage markers, TK1 expression analysis, thymidine supplementation rescue, Fhit knockout mouse tissue analysis PLoS genetics High 23209436
2012 Silencing Fhit gene expression in MHC-I-positive tumor cells causes transcriptional down-regulation of antigen-processing machinery (APM) components and MHC-I heavy chains, reducing MHC-I surface expression. Transfection of Fhit into MHC-I-negative tumor cells restores MHC-I surface expression. siRNA knockdown, FHIT transfection, flow cytometry, RT-PCR The Journal of pathology Medium 22451343
2014 FHIT suppresses EMT and metastasis in lung cancer through upregulation of miR-30c, which directly targets metastasis genes MTDH, HMGA2, VIM, and FN1. In vivo metastasis assay, in vitro migration/invasion assay, miRNA target validation, gain/loss of function experiments PLoS genetics Medium 25340791
2009 Nit1 and Fhit tumor suppressor activities are additive in vivo; double Fhit(-/-)Nit1(-/-) knockout mice develop more tumors than Fhit(-/-) mice alone, suggesting they act in distinct pathways in mammals. Both Nit1 and Fhit localize to cytoplasm and mitochondria but not nuclei. Double knockout mouse tumor susceptibility assay, subcellular fractionation/localization, cell stress assays Journal of cellular biochemistry Medium 19479888
2012 Fhit function in suppressing DNA damage requires a functional HIT domain and the Y114 residue, is independent of Atr or Atm kinases, but is dependent on Chk1 kinase activity, suggesting Fhit and Chk1 cooperate to prevent replication stress-induced DNA damage. Mutant expression studies, kinase inhibitor experiments, DNA damage assays in Fhit-deficient cells Advances in biological regulation Medium 23102829
2015 Fhit loss-induced DNA damage (via reduced TK1 and replication stress) creates optimal substrates for APOBEC3B-mediated mutagenesis; FHIT-low/APOBEC3B-high lung adenocarcinomas display significantly increased APOBEC signature mutations. Thymidine supplementation (rescuing nucleotide balance) decreases APOBEC-induced TP53 mutations in FHIT-low cells. TCGA data analysis, in vitro FHIT silencing, TP53 mutation analysis, thymidine rescue experiments Oncotarget Medium 25401976
2019 FHIT functions as a BMPR2 modifier; reduced FHIT expression is associated with endothelial and smooth muscle cell dysfunction in pulmonary arterial hypertension. Fhit-/- mice develop exaggerated hypoxic pulmonary hypertension. Enzastaurin upregulates FHIT expression and reverses experimental pulmonary hypertension. siRNA high-throughput screen, Fhit knockout mouse model, pharmacological rescue (enzastaurin), in vitro cell dysfunction assays American journal of respiratory and critical care medicine Medium 30107138
1997 Fhit protein is localized to the cytosolic compartment in renal tubular epithelium, as determined by immunofluorescence and biochemical fractionation. Immunofluorescence, biochemical subcellular fractionation The American journal of pathology Medium 9403704
2001 Fhit protein is localized to the nucleus and plasma membrane in rat tissues, as determined by subcellular fractionation of multiple tissues. Biochemical fractionation, immunoblot analysis of subcellular fractions Molecular and cellular biochemistry Low 11768238
2017 Fhit expression impacts translation of hundreds of cancer-associated mRNAs, including changes in 5'-UTR ribosome occupancy; this is consistent with Fhit's enzymatic ability to degrade m7GpppN caps generated during 3'-5' mRNA decay, potentially affecting translational regulation. Ribosome profiling (ribosome occupancy assay) in Fhit-positive vs. Fhit-negative cells Molecular cancer Medium 29282095
2023 Acetylcholine promotes lung adenocarcinoma cell migration and invasion via the α5-nAChR/DNMT1/FHIT axis; α5-nAChR activation increases DNMT1 expression, which methylates and silences FHIT, promoting EMT. In vivo chronic stress mouse model, in vitro cell migration/invasion assays, DNMT1 overexpression/silencing, FHIT methylation analysis Cellular and molecular life sciences : CMLS Medium 37029227

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 The FHIT gene 3p14.2 is abnormal in lung cancer. Cell 545 8620533
1997 Replacement of Fhit in cancer cells suppresses tumorigenicity. Proceedings of the National Academy of Sciences of the United States of America 343 9391102
2011 Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature 335 21258320
1996 The FHIT gene at 3p14.2 is abnormal in breast carcinomas. Cancer research 235 8764101
1996 FRA3B extends over a broad region and contains a spontaneous HPV16 integration site: direct evidence for the coincidence of viral integration sites and fragile sites. Human molecular genetics 224 8824874
1998 Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction. Human molecular genetics 201 9499431
2000 Muir-Torre-like syndrome in Fhit-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 181 10758156
1998 The role of the FHIT/FRA3B locus in cancer. Annual review of genetics 169 9928473
2005 Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. Oncogene 168 15674328
2001 FHIT gene therapy prevents tumor development in Fhit-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 142 11248081
1997 Chromosome 3p14 homozygous deletions and sequence analysis of FRA3B. Human molecular genetics 135 9063739
1998 The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. Proceedings of the National Academy of Sciences of the United States of America 128 9689122
2004 The fragile genes FHIT and WWOX are inactivated coordinately in invasive breast carcinoma. Cancer 121 15073846
2000 Altered expression of Fhit in carcinoma and precarcinomatous lesions of the esophagus. Cancer research 121 10728669
1997 Sequence of the FRA3B common fragile region: implications for the mechanism of FHIT deletion. Proceedings of the National Academy of Sciences of the United States of America 117 9405656
1999 Cancer-specific chromosome alterations in the constitutive fragile region FRA3B. Proceedings of the National Academy of Sciences of the United States of America 114 10377436
2002 FHIT: from gene discovery to cancer treatment and prevention. The Lancet. Oncology 111 12473516
2003 Cancer and the FRA3B/FHIT fragile locus: it's a HIT. British journal of cancer 103 12771912
2007 Replication stress induces tumor-like microdeletions in FHIT/FRA3B. Proceedings of the National Academy of Sciences of the United States of America 97 18162546
2014 The FHIT gene product: tumor suppressor and genome "caretaker". Cellular and molecular life sciences : CMLS 83 25283145
2012 Initiation of genome instability and preneoplastic processes through loss of Fhit expression. PLoS genetics 80 23209436
1999 Allele-specific late replication and fragility of the most active common fragile site, FRA3B. Human molecular genetics 80 9949202
1996 Aberrant FHIT transcripts in Merkel cell carcinoma. Cancer research 79 8653678
1998 An FHIT tumor suppressor gene? Genes, chromosomes & cancer 72 9559339
1996 Frequent breakpoints in the 3p14.2 fragile site, FRA3B, in pancreatic tumors. Cancer research 70 8813121
2007 The tumor suppressor Fhit acts as a repressor of beta-catenin transcriptional activity. Proceedings of the National Academy of Sciences of the United States of America 69 18077326
2005 Roles of FHIT and WWOX fragile genes in cancer. Cancer letters 69 16225988
1998 Nitrilase and Fhit homologs are encoded as fusion proteins in Drosophila melanogaster and Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 64 9671749
2000 Loss of FHIT expression in transitional cell carcinoma of the urinary bladder. The American journal of pathology 62 10666370
1999 The FHIT gene is expressed in pancreatic ductular cells and is altered in pancreatic cancers. Cancer research 62 10096564
1998 The murine Fhit gene is highly similar to its human orthologue and maps to a common fragile site region. Cancer research 62 9699673
1998 Characterization of PKCI and comparative studies with FHIT, related members of the HIT protein family. Experimental cell research 62 9770345
2014 FHIT suppresses epithelial-mesenchymal transition (EMT) and metastasis in lung cancer through modulation of microRNAs. PLoS genetics 61 25340791
2004 Fhit is a physiological target of the protein kinase Src. Proceedings of the National Academy of Sciences of the United States of America 61 15007172
2000 The expression of Fhit protein is related inversely to disease progression in patients with breast carcinoma. Cancer 60 10717620
2006 Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential. Oncogene 59 16407838
2009 Intramitochondrial calcium regulation by the FHIT gene product sensitizes to apoptosis. Proceedings of the National Academy of Sciences of the United States of America 58 19622739
2000 Fhit expression in gastric adenocarcinoma: correlation with disease stage and survival. Cancer 58 10618602
2015 Aberrant gene promoter methylation of p16, FHIT, CRBP1, WWOX, and DLC-1 in Epstein-Barr virus-associated gastric carcinomas. Medical oncology (Northwood, London, England) 55 25720522
2002 Direct correlation between FRA3B expression and cigarette smoking. Genes, chromosomes & cancer 54 12007194
2002 Evidence that instability within the FRA3B region extends four megabases. Oncogene 54 12483524
1999 Abnormal Fhit expression in malignant and premalignant lesions of the cervix. Cancer research 54 10537308
2001 Aberrations in the fragile histidine triad (FHIT) gene in idiopathic pulmonary fibrosis. Cancer research 53 11731438
2004 Hypermethylation of the 5' CpG island of the FHIT gene is associated with hyperdiploid and translocation-negative subtypes of pediatric leukemia. Cancer research 51 15026336
2004 Fhit-deficient normal and cancer cells are mitomycin C and UVC resistant. British journal of cancer 50 15494723
2000 Loss of fhit expression in invasive cervical carcinomas and intraepithelial lesions associated with invasive disease. Clinical cancer research : an official journal of the American Association for Cancer Research 50 10999736
2014 Identification of a tumor-suppressive human-specific microRNA within the FHIT tumor-suppressor gene. Cancer research 49 24556720
2002 High frequency of LOH, MSI and abnormal expression of FHIT in gastric cancer. European journal of cancer (Oxford, England : 1990) 49 11916557
2005 Involvement of the Fhit gene in the ionizing radiation-activated ATR/CHK1 pathway. Journal of cellular physiology 48 15389587
2003 Fragile site orthologs FHIT/FRA3B and Fhit/Fra14A2: evolutionarily conserved but highly recombinogenic. Proceedings of the National Academy of Sciences of the United States of America 47 14630947
1999 Reduced Fhit expression in sporadic and BRCA2-linked breast carcinomas. Cancer research 47 10363992
1997 Aphidicolin-induced FRA3B breakpoints cluster in two distinct regions. Genomics 47 9169152
1988 Translocation t(3;8)(p14.2;q24.1) in renal cell carcinoma affects expression of the common fragile site at 3p14(FRA3B) in lymphocytes. Cancer genetics and cytogenetics 44 3125959
2000 Differential susceptibility of renal carcinoma cell lines to tumor suppression by exogenous Fhit expression. Cancer research 43 10850413
2000 Alterations of the FHIT gene in human hepatocellular carcinoma. Cancer research 42 10706123
1997 FHIT gene alterations in esophageal cancer and ulcerative colitis (UC). Oncogene 41 9233782
2013 Promoter methylation of DAPK1, FHIT, MGMT, and CDKN2A genes in cervical carcinoma. International journal of clinical oncology 40 23494221
2020 RBP EIF2S2 Promotes Tumorigenesis and Progression by Regulating MYC-Mediated Inhibition via FHIT-Related Enhancers. Molecular therapy : the journal of the American Society of Gene Therapy 39 32059763
2007 A Fhit-ing role in the DNA damage checkpoint response. Cell cycle (Georgetown, Tex.) 39 17457056
2000 Abnormalities of the FHIT gene in human oral carcinogenesis. British journal of cancer 38 10732756
2006 Fhit modulates the DNA damage checkpoint response. Cancer research 36 17145874
2019 FHIT, a Novel Modifier Gene in Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine 35 30107138
2013 Replication stress induces specific enrichment of RECQ1 at common fragile sites FRA3B and FRA16D. Molecular cancer 35 23601052
2008 Alterations of FHIT and P53 genes in keratocystic odontogenic tumor, dentigerous and radicular cyst. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 35 18221322
2002 Multiple molecular alterations of FHIT in betel-associated oral carcinoma. The Journal of pathology 35 11857493
2010 Impaired replication dynamics at the FRA3B common fragile site. Human molecular genetics 34 19815620
2009 Fragile gene product, Fhit, in oxidative and replicative stress responses. Cancer science 34 19486340
2002 FHIT as tumor suppressor: mechanisms and therapeutic opportunities. Cancer biology & therapy 34 12432269
1998 Frequent homozygous deletions in the FRA3B region in tumor cell lines still leave the FHIT exons intact. Oncogene 32 9482109
2012 The tumour suppressor Fhit positively regulates MHC class I expression on cancer cells. The Journal of pathology 31 22451343
1997 The FHIT gene product is highly expressed in the cytoplasm of renal tubular epithelium and is down-regulated in kidney cancers. The American journal of pathology 31 9403704
1997 Frequent breakpoints in the region surrounding FRA3B in sporadic renal cell carcinomas. Oncogene 29 9178887
2004 Inactivation of the FHIT gene favors bladder cancer development. Clinical cancer research : an official journal of the American Association for Cancer Research 28 15569992
2002 Reciprocal translocations in breast tumor cell lines: cloning of a t(3;20) that targets the FHIT gene. Genes, chromosomes & cancer 28 12353263
1998 Analysis of FHIT transcripts in cervical and endometrial cancers. International journal of cancer 28 9537583
2013 Fhit deficiency-induced global genome instability promotes mutation and clonal expansion. PloS one 27 24244712
2005 Lung cancer susceptibility in Fhit-deficient mice is increased by Vhl haploinsufficiency. Cancer research 27 16061637
2014 Folate deficiency and FHIT hypermethylation and HPV 16 infection promote cervical cancerization. Asian Pacific journal of cancer prevention : APJCP 26 25422218
2008 Correlation of fragile histidine triad (Fhit) protein structural features with effector interactions and biological functions. The Journal of biological chemistry 26 19004824
2008 Hypermethylation of the 5'CpG island of the FHIT gene in clear cell renal carcinomas. Cancer letters 25 18378390
1999 FHIT gene abnormalities in both benign and malignant thyroid tumours. European journal of cancer (Oxford, England : 1990) 25 10448301
2015 FHIT loss-induced DNA damage creates optimal APOBEC substrates: Insights into APOBEC-mediated mutagenesis. Oncotarget 24 25401976
2001 Alterations of the FHIT gene in breast cancer: association with tumor progression and patient survival. Cancer detection and prevention 24 11425271
2017 Impact of FHIT loss on the translation of cancer-associated mRNAs. Molecular cancer 23 29282095
2004 CpG methylation in the Fhit regulatory region: relation to Fhit expression in murine tumors. Oncogene 23 15007387
2000 fhit Alterations in endometrial carcinoma and hyperplasia. International journal of cancer 23 10652418
1998 The role of deletions at the FRA3B/FHIT locus in carcinogenesis. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 23 10027001
2009 Nit1 and Fhit tumor suppressor activities are additive. Journal of cellular biochemistry 21 19479888
2015 Effect of FHIT loss and p53 mutation on HPV-infected lung carcinoma development. Oncology letters 20 26171037
2012 Inactivation of both FHIT and p53 cooperate in deregulating proliferation-related pathways in lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20 22425911
2000 Anomalous transcripts and allelic deletions of the FHIT gene in human esophageal cancer. Cancer genetics and cytogenetics 20 10812172
2007 Low expression of FHIT and PTEN correlates with malignancy of gastric carcinomas: tissue-array findings. Applied immunohistochemistry & molecular morphology : AIMM 19 18091387
2012 Characterization of the role of Fhit in suppression of DNA damage. Advances in biological regulation 18 23102829
1992 Detailed mapping around the breakpoint of (3;8) translocation in familial renal cell carcinoma and FRA3B. Genomics 18 1427857
2023 Acetylcholine promotes chronic stress-induced lung adenocarcinoma progression via α5-nAChR/FHIT pathway. Cellular and molecular life sciences : CMLS 17 37029227
2008 Frequent epigenetic silencing of the FHIT gene in penile squamous cell carcinomas. Virchows Archiv : an international journal of pathology 17 18299890
2011 microRNA-143 protects cells from DNA damage-induced killing by downregulating FHIT expression. Cancer biotherapy & radiopharmaceuticals 16 21711110
2003 Microsatellite instability is often observed in esophageal carcinoma patients with allelic loss in the FHIT/FRA3B locus. Oncology 16 12697969
2001 Distribution of Fhit protein in rat tissues and its intracellular localization. Molecular and cellular biochemistry 16 11768238
1999 Loss or reduction of Fhit expression in renal neoplasias: correlation with histogenic class. Human pathology 16 10571505