Changes in gene expression in SIRT3 knockout liver cells

Abstract

The sirtuin (SIRT) gene family is reported to regulate critical intracellular processes from aging to cellular metabolism and repair. SIRT3 knockout (SIRT3-/-) mice develop receptor positive mammary tumors starting at 13 months and SIRT3 expression is decreased in human breast cancer samples as well as several other diseases. It is established that carcinogenesis results from the accumulation of multiple aberrant genetic events including the activation of oncogenes and inactivation of tumor-suppressor genes. To determine the potential early genomic events that may play a role in the tumor-permissive phenotype observed in SIRT3-/- cells, we compared gene expression profile in SIRT3-/- and wild-type (SIRT3+/+) mouse livers. Differences between the expression profiles of genes important in the p53 and apoptosis pathway and signal transduction pathways, as well as genes involved with insulin and cholesterol metabolism, were determined. These results demonstrate that the expression of several oncogenes including Cdkn1, Myc, and Nos2 are increased. In contrast, several genes shown to be downregulated in human breast cancer including Btg2, Egr-1, Fos, Jun, Gadd4, and Wnt1 had decreased expression. The current work demonstrates that the loss of function of SIRT3 results in a cellular environment permissive for carcinogenesis and is characterized by altered metabolism.