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Cell Cycle. 2014;13(18):2913-30. doi: 10.4161/15384101.2014.946858.

A knockdown with smoke model reveals FHIT as a repressor of Heme oxygenase 1.

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a Department of Biochemistry and Program in Molecular and Cellular Biology; Carver College of Medicine ; University of Iowa ; Iowa City , IA USA.


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.


ARE, antioxidant response element; ApppA, diadenosine triphosphate; BACH1; BACH1, BTB and CNC homology 1 gene; BMC, bone marrow cell; CPT, camptothecin; CSE, cigarette smoke extract; Cigarette smoke; FHIT; FHIT, fragile histidine triad gene; HMOX1; HMOX1, heme oxygenase 1 gene; MMC, mitomycin C; NRF2; Nrf2, nuclear factor erythroid derived 2-like 2 protein; Oxidative Stress; RNAi, RNA interference; ROS, reactive oxygen species; qRT-PCR, quantitative real time PCR; siRNA, short interfering RNA

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