Dihydropyrimidine Accumulation is Required for the Epithelial-mesenchymal Transition

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Aug 30

PMID 25171410

Citations 131

Authors

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

Affiliations

Soon will be listed here.

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.

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