Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition | Zendy

Yoav D. Shaul | Zendy; Elizaveta Freinkman | Zendy; William C. Comb | Zendy; Jason R. Cantor | Zendy; Wai Leong Tam | Zendy; Prathapan Thiru | Zendy; DoHoon Kim | Zendy; Naama Kanarek | Zendy; Michael E. Pacold | Zendy; Walter W. Chen | Zendy; Brian Bierie | Zendy; Richard Possemato | Zendy; Ferenc Reinhardt | Zendy; Robert A. Weinberg | Zendy; Michael B. Yaffe | Zendy; David M. Sabatini | Zendy

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Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition

Author(s) -

Yoav D. Shaul,

Elizaveta Freinkman,

William C. Comb,

Jason R. Cantor,

Wai Leong Tam,

Prathapan Thiru,

DoHoon Kim,

Naama Kanarek,

Michael E. Pacold,

Walter W. Chen,

Brian Bierie,

Richard Possemato,

Ferenc Reinhardt,

Robert A. Weinberg,

Michael B. Yaffe,

David M. Sabatini

Publication year - 2014

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2014.07.032

Subject(s) - biology , dpyd , mesenchymal stem cell , epithelial–mesenchymal transition , cell growth , dihydropyrimidine dehydrogenase , cancer research , pyrimidine metabolism , cell , cell culture , microbiology and biotechnology , cancer cell , cancer , gene , genetics , biochemistry , enzyme , metastasis , fluorouracil , pharmacogenetics , purine , thymidylate synthase , genotype

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.

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