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.

Changes in the Expression and the Role of Sirtuin 3 in Cancer Cells and in Cardiovascular Health and Disease

“…These genes are often overexpressed in human cancers, primarily in breast tumors. In contrast, several genes that were previously reported to be downregulated in human breast cancer containing B-cell translocation gene 2 (BTG2), early growth response 1 (EGR1), and Gadd4 had decreased expression with larger than 2-folds in the SIRT3-deficient hepatocytes [66]. The list of genes with larger than 2-folds in the cancer-associated pathways and genes associated with insulinlipoprotein-cholesterol metabolism is presented in Figure 1.…”

“…We have previously shown that the loss of expression of SIRT3 in mouse liver and cultured mouse embryonic fibroblasts results in a cellular environment susceptible to carcinogenesis and cellular transformation [38,66]. In the subsequent study, we investigated how SIRT3 alters the gene expression of cancer-related pathways in SIRT3 wild-type and SIRT3 knockout mouse hepatocytes.…”

“…Mitochondria are critical in regulating oxidative stress signaling during cardiovascular Figure 1. Changes in the expression of p53, signal transduction pathway, and insulin-lipoprotein-cholesterol genes in SIRT3-deficient livers compared to SIRT3 wild-type mouse based on [66].…”

“…In the subsequent study, we investigated how SIRT3 alters the gene expression of cancer-related pathways in SIRT3 wild-type and SIRT3 knockout mouse hepatocytes. We studied how deficiency of SIRT3 expression might change the gene expression profile of various transcription factors and proteins linked to tumor formation in addition to genes associated with metabolism using a commercially available real-time polymerase chain reaction kit that screens gene expression profiling of diverse pathways [66]. We found upregulated expression of several genes having oncogenic properties including cyclin-dependent kinase inhibitor 1A P21 (Cdkn1a), myelocytomatosis oncogene (Myc), and nitric oxide synthase (NOS2) in SIRT3-deficient mouse liver.…”

Deacetylation of Androgen Receptor by SIRT2 and its Dysregulation Promotes Pathogenesis and Progression of Prostate Cancer

“…Seven SIRTs are found in different compartments within the cells. SIRT3, 4 and 5 are located in the mitochondria, SIRT1, 6 and 7 are mainly located in the nuclei, and SIRT2 is primarily located in the cytoplasm but it can translocate into the nucleus during cell cycle 12 . SIRTs have been reported to be involved in aging, longevity, stress response, regulation of metabolism, gene silencing, and DNA repair.…”