Colon and prostate tumorigenesis can be driven by aberrantly regulated beta-catenin. Caloric restriction (CR) increases lifespan of multiple organisms and delays tumorigenesis in mouse models of colon and prostate cancer. Preliminary data indicate that SIRT1, a protein deacetylase that is necessary and sufficient for the anti-aging affects of CR, deacetylates P-catenin and regulates p-catenin mediated gene transcription. Acetylation of B-catenin differentially regulates its ability to induce gene transcription. This proposal is designed to test the hypothesis that SIRT1 negatively regulates B-catenin mediated tumorigenesis. The experiments are designed to demonstrate that SIRT1 decreases the ability of B-catenin to induce transcription of Wnt target genes, which promote tumorigenesis, by inhibiting its association with the T-Cell Factor (TCP) transcription factor. Recently, it has been demonstrated that P-catenin positively regulates other transcription factors which have tumor suppressing functions. Using gene expression profiling of cells expressing SIRT1, this proposal examines whether SIRT1 induces B-catenin to switch from promoting the transcription of tumor promoting genes to genes that suppress the development of tumors. Finally, the role of SIRT1 in tumorigenesis is examined in mouse models of P-catenin mediated tumorigenesis. These experiments provide the foundation for understanding the potential role of the anti-aging protein SIRT1 in suppressing the development of cancer. More importantly it provides the basis for designing drugs that preferentially activate SIRT1 for the treatment of P-catenin mediated cancers. SIRT1 does not have negative affects on normal cells; therefore, use of such therapies would preferentially target cancer cells. ? ? ?
| Bell, Eric L; Nagamori, Ippei; Williams, Eric O et al. (2014) SirT1 is required in the male germ cell for differentiation and fecundity in mice. Development 141:3495-504 |
| Simic, Petra; Williams, Eric O; Bell, Eric L et al. (2013) SIRT1 suppresses the epithelial-to-mesenchymal transition in cancer metastasis and organ fibrosis. Cell Rep 3:1175-86 |
| Fendt, Sarah-Maria; Bell, Eric L; Keibler, Mark A et al. (2013) Reductive glutamine metabolism is a function of the ?-ketoglutarate to citrate ratio in cells. Nat Commun 4:2236 |
| Simic, Petra; Zainabadi, Kayvan; Bell, Eric et al. (2013) SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating ?-catenin. EMBO Mol Med 5:430-40 |
