Genome-wide changes accompanying knockdown of fatty acid synthase in breast cancer - PubMed (original) (raw)

Genome-wide changes accompanying knockdown of fatty acid synthase in breast cancer

Lynn M Knowles et al. BMC Genomics. 2007.

Abstract

Background: The lipogenic enzyme fatty acid synthase (FAS) is up-regulated in a wide variety of cancers, and is considered a potential metabolic oncogene by virtue of its ability to enhance tumor cell survival. Inhibition of tumor FAS causes both cell cycle arrest and apoptosis, indicating FAS is a promising target for cancer treatment.

Results: Here, we used gene expression profiling to conduct a global study of the cellular processes affected by siRNA mediated knockdown of FAS in MDA-MB-435 mammary carcinoma cells. The study identified 169 up-regulated genes (> or = 1.5 fold) and 110 down-regulated genes (< or = 0.67 fold) in response to knockdown of FAS. These genes regulate several aspects of tumor function, including metabolism, cell survival/proliferation, DNA replication/transcription, and protein degradation. Quantitative pathway analysis using Gene Set Enrichment Analysis software further revealed that the most pronounced effect of FAS knockdown was down-regulation in pathways that regulate lipid metabolism, glycolysis, the TCA cycle and oxidative phosphorylation. These changes were coupled with up-regulation in genes involved in cell cycle arrest and death receptor mediated apoptotic pathways.

Conclusion: Together these findings reveal a wide network of pathways that are influenced in response to FAS knockdown and provide new insight into the role of this enzyme in tumor cell survival and proliferation.

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Figures

Figure 1

Figure 1

FAS knockdown generates specific and time-dependent gene expression patterns. (a-c) Target mRNA, protein and fatty acid biosynthesis knockdown by FAS siRNA duplexes. MDA-MB-435 tumor cells were exposed to 25 nM of four different siRNA duplexes targeted against FAS (FAS #1-#4) or non-silencing control siRNA for 48 h. Efficiency of FAS knockdown was determined by measuring FAS mRNA (a), FAS protein (b) and fatty acid biosynthesis (c). β-tubulin served as a loading control for FAS protein expression. Values are the mean ± SE of two replicates per treatment. (d) Expression profile represents 279 genes differentially modified by 1.5 fold in response to knockdown of FAS (shown in hours on the X-axis). Horizontal lines represent the average expression of individual genes modified by at least 3 of the FAS siRNA duplexes. Red and green indicate increased and decreased expression, respectively, relative to non-silencing control siRNA.

Figure 2

Figure 2

Down-regulation of metabolic pathways by targeted knockdown of FAS. The figure displays select pathways found to be down-regulated in response to FAS siRNA treatment compared to non-silencing control siRNA. Significance was determined using a nominal _p_-value < 0.05 or FDR < 0.250. The expression levels of the genes significantly modified in the pathway are coded colorimetrically: red, high expression; blue, low expression. FAS siRNA treatments for each time point are ordered as follows (a and b indicate different biological replicates): FAS #1a, FAS #1b, FAS #2a, FAS #2b, FAS #3a, FAS #3b, FAS #4a, FAS #4b. For a complete list of all pathways down-regulated by knockdown of FAS, see Additional File 6.

Figure 3

Figure 3

Up-regulation of cell cycle arrest and cell death pathways in response to knockdown of FAS. The figure displays select pathways found to be up-regulated in response to FAS siRNA treatment compared to non-silencing control siRNA. Significance was determined using a nominal _p_-value < 0.05 or FDR < 0.250. The expression levels of the genes significantly modified in the pathway are coded colorimetrically: red, high expression; blue, low expression. FAS siRNA treatments for each time point are ordered as follows (a and b indicate different biological replicates): FAS #1a, FAS #1b, FAS #2a, FAS #2b, FAS #3a, FAS #3b, FAS #4a, FAS #4b. For a complete list of all pathways up-regulated by knockdown of FAS, see Additional File 7.

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