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.