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A knockdown with smoke model reveals FHIT as a repressor of Heme oxygenase 1
Journal article   Open access   Peer reviewed

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

Jennifer A Boylston and Charles Brenner
Cell Cycle, Vol.13(18), pp.2913-2930
09/17/2014
DOI: 10.4161/15384101.2014.946858
PMCID: PMC4614990
PMID: 25486479
url
https://doi.org/10.4161/15384101.2014.946858View
Published (Version of record) Open Access

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.
 HMOX1 NRF2 Oxidative Stress BACH1 FHIT Cigarette smoke

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