Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition

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

来源：Cell, 2014, 158(5): 1094-1109.

DOI：10.1016/j.cell.2014.07.032

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.

• 出版日期2014-8-28