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Published on: August 28, 2009
A knockdown with smoke model reveals FHIT as a repressor of Heme oxygenase 1
Jennifer A Boylston1, Charles Brenner
1a Department of Biochemistry and Program in Molecular and Cellular Biology; Carver College of Medicine ; University of Iowa ; Iowa City , IA USA.
Abstract:
Fragile histidine triad (FHIT) gene deletions are among the earliest and most frequent events in carcinogenesis, particularly in carcinogen-exposed tissues. Though FHIT has been established as an authentic tumor suppressor, the mechanism underlying tumor suppression remains opaque. Most experiments designed to clarify FHIT function have analyzed the consequence of re-expressing FHIT in FHIT-negative cells. However, carcinogenesis occurs in cells that transition from FHIT-positive to FHIT-negative. To better understand cancer development, we induced FHIT loss in human bronchial epithelial cells with RNA interference. Because FHIT is a demonstrated target of carcinogens in cigarette smoke, we combined FHIT silencing with cigarette smoke extract (CSE) exposure and measured gene expression consequences by RNA microarray. The data indicate that FHIT loss enhances the expression of a set of oxidative stress response genes after exposure to CSE, including the cytoprotective enzyme heme oxygenase 1 (HMOX1) at the RNA and protein levels. Data are consistent with a mechanism in which Fhit protein is required for accumulation of the transcriptional repressor of HMOX1, Bach1 protein. We posit that by allowing superinduction of oxidative stress response genes, loss of FHIT creates a survival advantage that promotes carcinogenesis.
Insights
Loss of the Fragile Histidine Triad (FHIT) gene in bronchial cells enhances oxidative stress gene expression after cigarette smoke exposure. This may promote cancer development by providing a survival advantage.
Area of Science:
- Oncology
- Molecular Biology
- Environmental Health
Background:
- Fragile Histidine Triad (FHIT) gene deletions are early events in carcinogenesis, particularly in carcinogen-exposed tissues.
- FHIT is a known tumor suppressor, but its mechanism of action is not fully understood.
- Carcinogenesis involves a transition from FHIT-positive to FHIT-negative cells, a process not well-modeled by re-expression studies.
Purpose of the Study:
- To investigate the functional consequences of FHIT loss in human bronchial epithelial cells.
- To understand the role of FHIT in carcinogenesis, especially in response to cigarette smoke exposure.
- To elucidate the molecular mechanisms by which FHIT loss contributes to cancer development.
Main Methods:
- FHIT gene loss was induced in human bronchial epithelial cells using RNA interference.
- Cells were exposed to cigarette smoke extract (CSE) to mimic carcinogen exposure.
- Gene expression changes were analyzed using RNA microarray, with specific focus on oxidative stress response genes.
Main Results:
- FHIT loss enhanced the expression of oxidative stress response genes, including heme oxygenase 1 (HMOX1), at both RNA and protein levels following CSE exposure.
- Data suggest FHIT protein is necessary for the accumulation of Bach1, a transcriptional repressor of HMOX1.
- FHIT deficiency leads to increased expression of oxidative stress genes, potentially creating a pro-survival advantage.
Conclusions:
- Loss of FHIT function in bronchial cells potentiates the oxidative stress response to cigarette smoke components.
- This enhanced response, driven by impaired Bach1 repression, may confer a survival advantage to cells, promoting carcinogenesis.
- Understanding FHIT's role in oxidative stress response is crucial for developing strategies against smoking-related cancers.
