The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth

Arvin M. Gouw, Katherine Margulis, Natalie S. Liu, Sudha J. Raman, Anthony Mancuso, Georgia G. Toal, Ling Tong, Adriane Mosley, Annie L. Hsieh, Delaney K. Sullivan, Zachary E. Stine, Brian J. Altman, Almut Schulze, Chi V. Dang*, Richard N. Zare, Dean W. Felsher

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

Abstract

Lipid metabolism is frequently perturbed in cancers, but the underlying mechanism is unclear. We present comprehensive evidence that oncogene MYC, in collaboration with transcription factor sterol-regulated element-binding protein (SREBP1), regulates lipogenesis to promote tumorigenesis. We used human and mouse tumor-derived cell lines, tumor xenografts, and four conditional transgenic mouse models of MYC-induced tumors to show that MYC regulates lipogenesis genes, enzymes, and metabolites. We found that MYC induces SREBP1, and they collaborate to activate fatty acid (FA) synthesis and drive FA chain elongation from glucose and glutamine. Further, by employing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we observed in vivo lipidomic changes upon MYC induction across different cancers, for example, a global increase in glycerophosphoglycerols. After inhibition of FA synthesis, tumorigenesis was blocked, and tumors regressed in both xenograft and primary transgenic mouse models, revealing the vulnerability of MYC-induced tumors to the inhibition of lipogenesis. Gouw and Margulis et al. present comprehensive evidence that the oncogene MYC collaborates with the transcription factor SREBP1 in controlling lipogenesis to promote tumorigenesis. Utilizing multiple MYC-induced tumor models, they both identify key lipogenesis genes, enzymes, and metabolites affected by MYC and expose the vulnerability of MYC cancers to lipogenesis inhibition.

Original languageAmerican English
Pages (from-to)556-572.e5
JournalCell Metabolism
Volume30
Issue number3
DOIs
StatePublished - 3 Sep 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • ChIP
  • MYC
  • MYC conditional transgenic mouse models
  • RNA-seq
  • SREBP1
  • acetyl-CoA carboxylase A inhibition
  • carbon tracing
  • fatty acid synthesis
  • glycerophosphoglycerols
  • mass spectrometry imaging
  • nuclear run-on

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