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.

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Notes/Citation Information

Published in Cell Reports, v. 21, issue 13, p. 3807-3818.

© 2017 The Author(s).

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Funding Information

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.

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The accession number for the microarray data reported in this paper is GEO: GSE93762.

Supplemental Information includes Supplemental Experimental Procedures, seven figures, and five tables and can be found with this article online at https://doi.org/10.1016/j.celrep.2017.11.103.

PIIS2211124717317874_mmc1.pdf (77554 kB)
Document S1. Supplemental Experimental Procedures and Figures S1–S7

PIIS2211124717317874_mmc2.xlsx (68 kB)
Table S1. Quantitative Mass Spectrometry of Lipid Extracts from 13 Disomes, Related to Figure 1

PIIS2211124717317874_mmc3.xlsx (26 kB)
Table S2. Quantitative High-Performance Liquid Chromatography of Long-Chain Bases, Related to Figure 1

PIIS2211124717317874_mmc4.xlsx (53 kB)
Table S3. Genes Involved in the Regulation of Sphingolipid Biosynthesis, Related to Figure 3

PIIS2211124717317874_mmc5.xlsx (1485 kB)
Table S4. Transcriptome Profiles of the Disomes Harboring the LCB3 Deletion, Related to Figure 6

PIIS2211124717317874_mmc6.xlsx (288 kB)
Table S5. Proteome Profiles of the Disomes Harboring the LCB3 Deletion, Related to Figure 7