p53 represses the mevalonate pathway to mediate tumor suppression Journal Article

Authors: Moon, S. H.; Huang, C. H.; Houlihan, S. L.; Regunath, K.; Freed-Pastor, W. A.; Morris, J. P. 4th; Tschaharganeh, D. F.; Kastenhuber, E. R.; Barsotti, A. M.; Culp-Hill, R.; Xue, W.; Ho, Y. J.; Baslan, T.; Li, X.; Mayle, A.; de Stanchina, E.; Zender, L.; Tong, D. R.; D'Alessandro, A.; Lowe, S. W.; Prives, C.
Article Title: p53 represses the mevalonate pathway to mediate tumor suppression
Abstract: There are still gaps in our understanding of the complex processes by which p53 suppresses tumorigenesis. Here we describe a novel role for p53 in suppressing the mevalonate pathway, which is responsible for biosynthesis of cholesterol and nonsterol isoprenoids. p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene. A mouse model of liver cancer reveals that downregulation of mevalonate pathway gene expression by p53 occurs in premalignant hepatocytes, when p53 is needed to actively suppress tumorigenesis. Furthermore, pharmacological or RNAi inhibition of the mevalonate pathway restricts the development of murine hepatocellular carcinomas driven by p53 loss. Like p53 loss, ablation of ABCA1 promotes murine liver tumorigenesis and is associated with increased SREBP-2 maturation. Our findings demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated liver tumor suppression and outline the mechanism by which this occurs. © 2018 Elsevier Inc. The mevalonate pathway is selectively vulnerable in tumors lacking p53. © 2018 Elsevier Inc.
Keywords: liver cell carcinoma; nonhuman; cell proliferation; mouse; gene targeting; cell cycle progression; apoptosis; gene expression; cell growth; protein degradation; protein depletion; protein targeting; animal experiment; animal model; gene locus; genotype; protein p53; carcinogenesis; cancer inhibition; chromatin immunoprecipitation; cancer cell; liver cancer; down regulation; cholesterol; upregulation; liver cell; short hairpin rna; oncogene myc; liver weight; p53; tumor suppression; tumor microenvironment; metabolomics; steroidogenesis; cancer metabolism; cholesterol synthesis; mevalonic acid; abc transporter a1; mevalonate pathway; priority journal; article; abca1; srebp-2; sterol regulatory element binding protein 2
Journal Title: Cell
Volume: 176
Issue: 3
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2019-01-24
Start Page: 564
End Page: 580.e8
Language: English
DOI: 10.1016/j.cell.2018.11.011
PUBMED: 30580964
PROVIDER: scopus
PMCID: PMC6483089
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
Citation Impact
MSK Authors
  1. Scott W Lowe
    204 Lowe
  2. Chun-Hao   Huang
    21 Huang
  3. Timour Baslan
    34 Baslan
  4. Yu-jui Ho
    20 Ho
  5. Allison Mayle
    4 Mayle
  6. Xiang Li
    5 Li