Tumor suppressor genes (TSGs) elicit carcinogenic phenotypes by gene loss. In thousands of publications, however, TSGs have been assayed for activities by reintroduction into tumor cells with TSG deletions. Whereas the FHIT gene has been defined as a gene that causes programmed cell death when reintroduced to cancer cells, normal epithelial cells are FHIT+ and do not undergo signal or age-independent apoptosis. Because the FHIT gene is lost early, i.e., from premalignant bronchial epithelial cells, we determined the gene expression consequences of this event and discovered that FHIT gene inactivation increases expression of a set of proteins important in lung carcinogenesis including DNA methyltransferase 1 (Dnmt1), mitogen- activated protein kinase (Erk1) and nuclear factor Yalpha (NF-Yalpha). The mechanism of the increased mRNA and protein expression is specific stabilization of a set of normally unstable mRNAs. Moreover, increased expression of Dnmt1 is accompanied by an immediate and specific alteration in DNA methylation, which silences expression of a set of extracellularly localized tumor suppressors, including Ccn1, Ccn2 and Tgm2. Thus, our data indicate that the tumor suppressing function of Fhit involves limiting expression of oncoproteins by virtue of promoting specific mRNA decay and that Fhit loss initiates a gene expression and epigenetic cascade to promote carcinogenesis.
The specific aims of this project are: 1) To define the molecular steps by which Fhit depletion increases expression of Dnmt1 and other proteins. 2) To determine the relationship of Fhit-ApppA binding and hydrolytic activity to the function of Fhit as a regulator of expression of Dnmt1 and other proteins. 3) To define the genes that are individually and cooperatively dysregulated by loss of Fhit and gain of Dnmt1 in bronchial epithelial cells.
Lung cancer is the leading cause of cancer deaths worldwide. The long term aim of this project is to reduce cancer incidence by exploiting the consequences of loss of the FHIT gene from bronchial epithelia. Indeed, because loss of Fhit expression leads to gain of Dnmt1 expression, this research suggests that Dnmt1 inhibition in bronchial airways may be a rational cancer chemo-preventative strategy for smokers and former smokers. Even a 10% reduction in lung cancer incidence could save more than 16,000 U.S. lives per year.
|Boylston, Jennifer A; Brenner, Charles (2014) A knockdown with smoke model reveals FHIT as a repressor of Heme oxygenase 1. Cell Cycle 13:2913-30|
|Huang, J; Stewart, A; Maity, B et al. (2014) RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis. Oncogene 33:3604-11|
|Wu, Bo-Kuan; Mei, Szu-Chieh; Brenner, Charles (2014) RFTS-deleted DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation. Cell Cycle 13:3222-31|
|Wu, Bo-Kuan; Brenner, Charles (2014) Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation. Cell Rep 9:1827-40|
|Fagan, Rebecca L; Wu, Meng; Chédin, Frédéric et al. (2013) An ultrasensitive high throughput screen for DNA methyltransferase 1-targeted molecular probes. PLoS One 8:e78752|
|Fagan, Rebecca L; Cryderman, Diane E; Kopelovich, Levy et al. (2013) Laccaic acid A is a direct, DNA-competitive inhibitor of DNA methyltransferase 1. J Biol Chem 288:23858-67|
|Syeda, Farisa; Fagan, Rebecca L; Wean, Matthew et al. (2011) The replication focus targeting sequence (RFTS) domain is a DNA-competitive inhibitor of Dnmt1. J Biol Chem 286:15344-51|
|Linster, Carole L; Adler, Lital N; Webb, Kristofor et al. (2008) A second GDP-L-galactose phosphorylase in arabidopsis en route to vitamin C. Covalent intermediate and substrate requirements for the conserved reaction. J Biol Chem 283:18483-92|
|Robu, Mara E; Larson, Jon D; Nasevicius, Aidas et al. (2007) p53 activation by knockdown technologies. PLoS Genet 3:e78|
|Linster, Carole L; Gomez, Tara A; Christensen, Kathryn C et al. (2007) Arabidopsis VTC2 encodes a GDP-L-galactose phosphorylase, the last unknown enzyme in the Smirnoff-Wheeler pathway to ascorbic acid in plants. J Biol Chem 282:18879-85|
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