Effect of exogenous E2F-1 on the expression of common chromosome fragile site genes, FHIT and WWOX

Abstract

The expression of two tumor suppressor genes, fragile histidine triad (FHIT) and WW domain containing oxidoreductase (WWOX), encompassing common chromosome fragile regions, FRA3B at 3p14.2 and FRA16D at 16q23, is altered in many epithelial tumors. Since DNA sequence search shows that the FHIT gene has the E2F-1 recognition site in 5'] region, which regulates cell cycle, we tested the effect of E2F-1 overexpression in tumor cells. Ectopic E2F-1 expression led to an increase of Fhit and Wwox expression in allele remaining tumor cells and resulted in induction of apoptosis. Reporter assay showed that the E2F-1 site in FHIT 5' region was involved in the down-stream transcription after exogenous E2F-1 introduction. Chromatin immunoprecipitation detected exogenous E2F-1 binding to the recognition site in FHIT 5' region. The data suggest that E2F-1 overexpression plays a role in suppression of tumor, at least in part trough transcriptional regulation of FHIT and relevant activation of WWOX.