Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness of aneuploid cells. Remarkably, the fitness of aneuploid cells improves or deteriorates upon genetically decreasing or increasing ceramides, respectively. Combined targeting of serine and sphingolipid synthesis could be exploited to specifically target cancer cells, the vast majority of which are aneuploid. Hwang et al. demonstrate that aneuploid yeast cells rely on the synthesis of the amino acid serine for their viability. Serine is used for the synthesis of sphingolipids that control the fitness of aneuploid cells. Aneuploid cells are vulnerable to combined inhibition of serine and sphingolipid biosynthesis.
|Number of pages||12|
|State||Published - Dec 26 2017|
Bibliographical noteFunding Information:
We are thankful to Sofia Ordonez, Raquelle Torres, and Aracelli Acevedo for technical assistance. We are grateful to Jennifer Benanti and Angelika Amon for reagents. We thank Nada Kalaany for critical reading of the manuscript. This research was supported by the Richard and Susan Smith Family Foundation ( s67400000023429 ) and the Searle Scholars Program ( 13-ssp-268 ) to E.M.T. This work was also supported by a grant from the NIH ( 1R01GM118481-01A1 ) to E.M.T.
© 2017 The Author(s)
- genomic istability
- long-chain bases
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)