FHIT (Fragile Histidine Triad)
2006-12-01 Teresa Druck , Kay Huebner AffiliationBRT Rm. 940, 460 W. 12th Ave, Columbus, OH 43210
DNA/RNA
Depiction of the more than 1.67 Mb FHIT gene genomic locus with coding exons 5 through 9 (dark purple) and untranslated exons 1-4 and 10 (light purple). The position of the familial kidney cancer associated chromosome translocation is also shown.
Description
The FHIT gene spans more than 1.6 Mb of genomic DNA and is composed of 10 exons.
Transcription
The FHIT gene encodes a 1.1 kb mRNA which is expressed at low levels in most tissue types. FHIT encompasses the common fragile site FRA3B, where carcinogen-induced damage can lead to deletions, translocations and subsequent aberrant transcripts. Aberrant transcripts from this gene have been found in about half of all esophageal carcinomas, stomach carcinomas, and other carcinomas.
Pseudogene
A pseudogene, with sequences nearly identical to the 5UTR of FHIT, is located on chromosome 1.
Proteins
Description
FHIT encodes a 147 amino acid (16.8 kDa) protein that can be phosphorylated at tyrosine 114 by Src family proteins.
Expression
Fhit is expressed at low to moderate levels in most tissue types, with kidney and liver expressing the highest steady state levels
Localisation
Fhit is primarily located in the cytosol, but is also found in the mitochondria.
Function
Fhit protein is a tumor suppressor with reduced or no expression in many types of cancer. Fhit expression is more frequently lost in cancers of individuals with familial mutations causing deficiency in DNA repair genes such as BRCA1 and BRCA2 and MSH2. In vitro Fhit acts as a hydrolase that cleaves diadenosine triphosphate (Ap3A) to ADP and AMP. The Fhit-Ap3A enzyme-substrate complex appears to be the tumor suppressor signal. Restoration of Fhit expression in Fhit-deficient cancer cells causes death by apoptosis, involving the intrinsic caspase pathway, in cancer-derived cells and in tumor xenografts.
Homology
Fhit is similar to a yeast enzyme, diadenosine tetraphosphate (Ap4A) hydrolase and is a member of the large HIT family of proteins characterized by the histidine triad motif, HxHxHxx (where x is a hydrophobic residue).
Mutations
Note
The following FHIT polymorphisms have been described:
524 A/G (exon 6) silent
545 G/A (exon 6) silent
626 C/T (exon 7) silent
651 G/T (exon 8) valine to phenylalanine
656 T/C (exon 8) silent
several intronic splice regions
524 A/G (exon 6) silent
545 G/A (exon 6) silent
626 C/T (exon 7) silent
651 G/T (exon 8) valine to phenylalanine
656 T/C (exon 8) silent
several intronic splice regions
Somatic
No bona fide somatic point mutations thus far confirmed.
Implicated in
Entity name
Various types of cancer
Disease
Loss of expression occurs in more than 60% of human cancers; loss is very early in some cancers such as lung cancer. In a large, 4 generation family, a balanced translocation between FHIT (in intron 3) at 3p14.2 and TRC8, a patched related gene, at chromosome 8q24 is associated with bilateral, multifocal clear cell kidney carcinoma. Also, microsatellite loci within the FHIT gene, were shown to be closely linked to a gene that contributes to susceptibility to familial prostate cancer.
Prognosis
There are numerous reports of association of Fhit loss with specific prognostic or other clinical features of specific types of cancer.
Cytogenetics
The FHIT locus is involved in translocations and deletions in some fraction of many types of cancer, likely due to the recombinogenicity of the fragile region within FHIT and subsequent selective growth or survival advantage of cells with reduced Fhit protein expression.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 9288768 | 1997 | Analysis of the FHIT gene and FRA3B region in sporadic breast cancer, preneoplastic lesions, and familial breast cancer probands. | Ahmadian M et al |
| 8794732 | 1996 | Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5"'-P1,P3-triphosphate hydrolase. | Barnes LD et al |
| 12119013 | 2002 | Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. | Brenner C et al |
| 10497298 | 1999 | The histidine triad superfamily of nucleotide-binding proteins. | Brenner C et al |
| 9543008 | 1997 | Purification and crystallization of complexes modeling the active state of the fragile histidine triad protein. | Brenner C et al |
| 10063967 | 1998 | FHITness and cancer. | Druck T et al |
| 9012482 | 1997 | Structure and expression of the human FHIT gene in normal and tumor cells. | Druck T et al |
| 11406559 | 2001 | Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer. | Dumon KR et al |
| 11170287 | 2001 | Translocation breakpoints in FHIT and FRA3B in both homologs of chromosome 3 in an esophageal adenocarcinoma. | Fang JM et al |
| 10758156 | 2000 | Muir-Torre-like syndrome in Fhit-deficient mice. | Fong LY et al |
| 9689122 | 1998 | The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. | Gemmill RM et al |
| 10027000 | 1998 | Instability at chromosomal fragile sites. | Glover TW et al |
| 15998374 | 2005 | Concordant loss of fragile gene expression early in breast cancer development. | Guler G et al |
| 12095833 | 2002 | Loss of fragile histidine triad (FHIT) expression and microsatellite instability in periocular sebaceous gland carcinoma in patients with Muir-Torre syndrome. | Holbach LM et al |
| 12771912 | 2003 | Cancer and the FRA3B/FHIT fragile locus: it's a HIT. | Huebner K et al |
| 9928473 | 1998 | The role of the FHIT/FRA3B locus in cancer. | Huebner K et al |
| 15674328 | 2005 | Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. | Iliopoulos D et al |
| 11245468 | 2001 | Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells. | Ishii H et al |
| 10416589 | 1999 | Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression. | Ji L et al |
| 15705877 | 2005 | Genetic linkage of prostate cancer risk to the chromosome 3 region bearing FHIT. | Larson GP et al |
| 8598045 | 1996 | The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. | Ohta M et al |
| 9576908 | 1998 | Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit. | Pace HC et al |
| 15007172 | 2004 | Fhit is a physiological target of the protein kinase Src. | Pekarsky Y et al |
| 12530066 | 2002 | Loss of heterozygosity at the FHIT gene in different solid human tumours and its association with survival in colorectal cancer patients. | Petursdottir TE et al |
| 16407838 | 2006 | Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential. | Semba S et al |
| 9391102 | 1997 | Replacement of Fhit in cancer cells suppresses tumorigenicity. | Siprashvili Z et al |
| 12574506 | 2003 | Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding. | Trapasso F et al |
| 12124341 | 2002 | The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers. | Turner BC et al |
| 12231533 | 2002 | Two-hit inactivation of FHIT by loss of heterozygosity and hypermethylation in breast cancer. | Yang Q et al |
| 11325823 | 2001 | 5' CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer. | Zöchbauer-Müller S et al |
| 11517343 | 2001 | The tumor spectrum in FHIT-deficient mice. | Zanesi N et al |
Other Information
Locus ID:
NCBI: 2272
MIM: 601153
HGNC: 3701
Ensembl: ENSG00000189283
Variants:
dbSNP: 2272
ClinVar: 2272
TCGA: ENSG00000189283
COSMIC: FHIT
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA130232992 | bevacizumab | Chemical | VariantAnnotation | not associated | PD | 29852030 | |
| PA164746012 | ranibizumab | Chemical | VariantAnnotation | not associated | PD | 29852030 | |
| PA444987 | Multiple Sclerosis | Disease | ClinicalAnnotation | associated | PD | 27001119 | |
| PA447321 | Depressive Disorder, Major | Disease | ClinicalAnnotation | associated | PD | ||
| PA450037 | interferon beta-1a | Chemical | ClinicalAnnotation | associated | PD | 27001119 | |
| PA450039 | interferon beta-1b | Chemical | ClinicalAnnotation | associated | PD | 27001119 | |
| PA452229 | antidepressants | Chemical | ClinicalAnnotation | associated | PD |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38234243 | 2024 | Integrated analysis of FHIT gene alterations in cancer. | 0 |
| 38234243 | 2024 | Integrated analysis of FHIT gene alterations in cancer. | 0 |
| 36766695 | 2023 | The Rosetta Stone Hypothesis-Based Interaction of the Tumor Suppressor Proteins Nit1 and Fhit. | 0 |
| 38069335 | 2023 | Expression of Tumor Suppressor FHIT Is Regulated by the LINC00173-SNAIL Axis in Human Lung Adenocarcinoma. | 0 |
| 36766695 | 2023 | The Rosetta Stone Hypothesis-Based Interaction of the Tumor Suppressor Proteins Nit1 and Fhit. | 0 |
| 38069335 | 2023 | Expression of Tumor Suppressor FHIT Is Regulated by the LINC00173-SNAIL Axis in Human Lung Adenocarcinoma. | 0 |
| 35254116 | 2022 | System analysis of FHIT in LUAD and LUSC: The expression, prognosis, gene regulation network, and regulation targets. | 3 |
| 36161592 | 2022 | Investigation of the expression levels of CDH1, FHIT, PTEN, and TTPAL genes in colorectal tumors. | 0 |
| 35254116 | 2022 | System analysis of FHIT in LUAD and LUSC: The expression, prognosis, gene regulation network, and regulation targets. | 3 |
| 36161592 | 2022 | Investigation of the expression levels of CDH1, FHIT, PTEN, and TTPAL genes in colorectal tumors. | 0 |
| 33437205 | 2021 | Fhit induces the reciprocal suppressions between Lin28/Let-7 and miR-17/92miR. | 4 |
| 34092254 | 2021 | Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases. | 8 |
| 34181717 | 2021 | Locus-specific transcription silencing at the FHIT gene suppresses replication stress-induced copy number variant formation and associated replication delay. | 10 |
| 34284702 | 2021 | rs73092672 allele T is significantly associated with the higher risk of breast cancer incidence. | 1 |
| 33437205 | 2021 | Fhit induces the reciprocal suppressions between Lin28/Let-7 and miR-17/92miR. | 4 |
Citation
Teresa Druck ; Kay Huebner
FHIT (Fragile Histidine Triad)
Atlas Genet Cytogenet Oncol Haematol. 2006-12-01
Online version: http://atlasgeneticsoncology.org/gene/192/fhit-(fragile-histidine-triad)
