Journal
CELL METABOLISM
Volume 30, Issue 3, Pages 556-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2019.07.012
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Funding
- National Cancer Institute [T32 CA196585]
- Stanford Center of Molecular Analysis and Design
- National Institutes of Health [R01 CA184384, U01 CA188383, R01 CA208735 PQ7, R01 CA051497, R01 CA057341]
- German Research Foundation [SCHU2670]
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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.
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