Journal
CELL REPORTS
Volume 29, Issue 1, Pages 89-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.08.087
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [26710005, 15H05325, 19H03496, 16H01567, 18H04797, 18H04897, 15H05912, 16K14605, 19K22553, 15K12139, hp170227]
- JSPS KAKENHI [JP16H06276]
- Takeda Science Foundation
- Kobayashi Foundation for Cancer Research
- MSD Life Science Foundation
- Project for Cancer Research and Therapeutic Evolution (P-CREAT)
- Japan Agency for Medical Research and Development (AMED) [16cm0106223h0001]
- Research on Regulatory Science of Pharmaceuticals and Medical Devices [18mk0101127h0001]
- AMED-CREST from the AMED [JP18gm0910005j0004]
- Grants-in-Aid for Scientific Research [19H03496, 19K22553, 16K14605, 15K12139, 18H04797, 15H05325, 16H01567, 26710005, 18H04897] Funding Source: KAKEN
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Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis. PEtn accumulation correlated with tumor growth under nutrient starvation. PCYT2 suppression was partially mediated by downregulation of the transcription factor ELF3. Furthermore, PCYT2 overexpression reduced PEtn levels and tumor growth. In addition, PEtn accumulation and PCYT2 downregulation in human breast tumors correlated with poor prognosis. Thus, we show that glutamine deprivation leads to tumor progression by regulating PE biosynthesis via the ELF3-PCYT2 axis. Furthermore, manipulating glutamine-responsive genes could be a therapeutic approach to limit cancer progression.
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