Fragile tumor suppressors: Dissection of signal pathways

Common fragile sites are conserved regions of mammalian chromosomes that are exquisitely sensitive to forming gaps or breaks on metaphase chromosomes after partial inhibition of DNA synthesis. Studies revealing that fragile sites and fragile site genes are deleted or rearranged in many cancer-derived cells have demonstrated the importance of these loci in genome instability in cancer. Our laboratory has primarily been working on two common fragile site genes, FHIT and WWOX, which are located at FRA3B and FRA16D, respectively, the two most frequently expressed and best-characterized fragile sites in the human genome. FHIT and WWOX are both tumor suppressor genes that frequently show reduction or loss of expression in various human cancers. In this research which is focused on identifying signal pathways affected by these tumor suppressors, we demonstrated that: (1) Fhit down-modulates the expression of a cell cycle regulatory protein, cyclin D1, in various cells and experimental conditions. Cyclin D1, an oncogenic protein up-regulated in many human cancers, was down-modulated by Fhit overexpression by contributing to degradation of cyclin D1 through the proteosome pathway. (2) The WWOX gene has a role in prostate cancer development; Wwox expression was reduced or lost in prostate cancer-derived cells and tissues, in part due to DNA hypermethylation in the WWOX regulatory region. Both WWOX mRNA and protein expression can be restored after inhibition of DNA methylation and histone deacetylation. Restoration of WWOX suppressed prostate cancer growth and induced apoptosis in vitro and in vivo . Furthermore, Wwox suppressed prostate cancer-derived cell growth through binding and cytoplasmic sequestration of the transcription factor Ap2gamma, preventing Ap2gamma from entering the nucleus to activate ErbB2, and blocking ErbB2-mediated androgen receptor signaling.