Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1094-1109
Number of pages16
JournalCell
Volume158
Issue number5
DOIs
StatePublished - 28 Aug 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology

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