p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression. p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression

We have discovered that loss of wild-type p53 correlates with elevated expression of mevalonate pathway genes in murine liver cancer and in human tumors. Mechanistically p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene, which inhibits SREBP-2 maturation. In mice the increase in mevalonate gene expression occurs in premalignant p53-null hepatocytes at a stage when p53 is needed to actively suppress tumorigenesis. Either RNAi mediated suppression of key genes in the mevalonate pathway or pharmacological inhibition of its rate-limiting enzyme restricts the development of mouse hepatocellular carcinomas driven by p53 loss. Conversely, like p53 loss, ablation of ABCA1 promotes tumorigenesis in a murine model and is associated with increased SREBP-2 maturation. Our findings thereby demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated tumor suppression and outline the mechanism by which this occurs. Overall design: 4 samples were analyzed in replicates of 2 conditions. 1. Control, p53 WT hepatocytes transduced with MYC transposons delivered by hydrodynamic tail vein injection and isolated 6 days after injection. 2. Experimental, p53 null hepatocytes transduced with MYC transposons delivered by hydrodynamic tail vein injection and isolated 6 days after injection.