Related Experiment Video
Updated: Jun 27, 2026
Genetic Profiling and Genome-Scale Dropout Screening to Identify Therapeutic Targets in Mouse Models of Malignant Peripheral Nerve Sheath Tumor
Published on: August 25, 2023
Fhit tumor suppressor: guardian of the preneoplastic genome
Flavia Pichiorri1, Tiziana Palumbo, Sung-Suk Suh
1Ohio State University Comprehensive Cancer Center, Department of Molecular Virology, Molecular Virology and Medical Genetics. 460 W 12th Avenue, 43210 Columbus, OH, USA.
Abstract:
Environmental agents induce intragenic alterations in the FRA3B/FHIT chromosome fragile site, resulting in fragile FHIT allele loss early in cancer development. Fhit knockout mice are predisposed to tumor development and Fhit gene therapy reduces tumor burden. Repair-deficient cancers are likely to be Fhit-deficient and Fhit-deficient cells show enhanced resistance to ultraviolet C, mitomycin C, camptothecin and oxidative stress-induced cell killing. Loss of Fhit leads to alterations in the DNA damage response checkpoint and contributes to DNA instability. Hsp60/Hsp10 are Fhit interactors, suggesting a direct role for Fhit in stress responses. Fhit also interacts with and stabilizes ferrodoxin reductase (Fdxr), a mitochondrial flavoprotein that transfers electrons from NADPH to cytochrome P450, suggesting a role for Fhit in the modulation of reactive oxygen species production and of genomic damage.
Insights
The FHIT gene is crucial for preventing cancer by maintaining DNA stability. Loss of FHIT function, due to environmental damage, leads to increased cancer risk and resistance to DNA-damaging agents.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Environmental agents can damage DNA at the FRA3B/FHIT fragile site, leading to FHIT (Fragile Histidine Triad) gene loss.
- FHIT gene loss is an early event in cancer development and is associated with tumor predisposition.
Purpose of the Study:
- To investigate the role of the FHIT gene in DNA damage response and cancer development.
- To explore the functional consequences of FHIT deficiency in cellular stress responses and genomic stability.
Main Methods:
- Analysis of intragenic alterations at the FRA3B/FHIT site.
- Assessment of tumor development in Fhit knockout mice.
- Evaluation of Fhit gene therapy efficacy.
- Characterization of Fhit-deficient cell responses to genotoxic stress (UVC, MMC, camptothecin, oxidative stress).
- Identification of Fhit interacting proteins (Hsp60/Hsp10, Fdxr).
Main Results:
- Loss of FHIT alleles occurs early in cancer development.
- Fhit knockout mice exhibit increased susceptibility to tumors; Fhit gene therapy reduces tumor burden.
- Fhit-deficient cells display enhanced resistance to multiple DNA-damaging agents and oxidative stress.
- FHIT deficiency disrupts DNA damage response checkpoints, leading to genomic instability.
- FHIT interacts with Hsp60/Hsp10 and stabilizes ferredoxin reductase (Fdxr), impacting reactive oxygen species (ROS) production.
Conclusions:
- The FHIT gene plays a critical role in maintaining genomic integrity and preventing cancer.
- FHIT deficiency compromises DNA damage response pathways and contributes to oncogenesis.
- FHIT's interaction with Hsp60/Hsp10 and Fdxr highlights its involvement in cellular stress response and ROS modulation.
Related Concept Videos
02:23Abnormal Proliferation
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...