Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition
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Sabatini_Dihydropyrimidine.pdf
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Author(s)
Freinkman, Elizaveta
Comb, William C.
Cantor, Jason R.
Tam, Wai Leong
Thiru, Prathapan
Kanarek, Naama
Bierie, Brian
Shaul, Yoav
Kim, Dohoon
Chen, Walter W.
Date Issued
August 2014
Journal
Cell
Publisher
Elsevier
Citation
Shaul, Yoav D.; Freinkman, Elizaveta; Comb, William C.; Cantor, Jason R.; Tam, Wai Leong; Thiru, Prathapan; Kim, Dohoon et al. “Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition.” Cell 158, no. 5 (August 2014): 1094–1109 © 2014 Elsevier Inc
Version
Author's final manuscript
Abstract
It is increasingly appreciated that oncogenic transformation alters cellular metabolism to facilitate cell proliferation, but less is known about the metabolic changes that promote cancer cell aggressiveness. Here, we analyzed metabolic gene expression in cancer cell lines and found that a set of high-grade carcinoma lines expressing mesenchymal markers share a unique 44 gene signature, designated the “mesenchymal metabolic signature” (MMS). A FACS-based shRNA screen identified several MMS genes as essential for the epithelial-mesenchymal transition (EMT), but not for cell proliferation. Dihydropyrimidine dehydrogenase (DPYD), a pyrimidine-degrading enzyme, was highly expressed upon EMT induction and was necessary for cells to acquire mesenchymal characteristics in vitro and for tumorigenic cells to extravasate into the mouse lung. This role of DPYD was mediated through its catalytic activity and enzymatic products, the dihydropyrimidines. Thus, we identify metabolic processes essential for the EMT, a program associated with the acquisition of metastatic and aggressive cancer cell traits.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology)
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.cell.2014.07.032
