Tetraploidy is a hallmark of cancer cells, and tetraploidy‐selective cell growth suppression is a potential strategy for targeted cancer therapy. However, how tetraploid cells differ from normal diploids in their sensitivity to anti‐proliferative treatments remains largely unknown. In this study, we found that tetraploid cells are significantly more susceptible to inhibitors of a mitotic kinesin (CENP‐E) than are diploids. Treatment with a CENP‐E inhibitor preferentially diminished the tetraploid cell population in a diploid–tetraploid co‐culture at optimum conditions. Live imaging revealed that a tetraploidy‐linked increase in unsolvable chromosome misalignment caused substantially longer mitotic delay in tetraploids than in diploids upon moderate CENP‐E inhibition. This time gap of mitotic arrest resulted in cohesion fatigue and subsequent cell death, specifically in tetraploids, leading to tetraploidy‐selective cell growth suppression. In contrast, the microtubule‐stabilizing compound paclitaxel caused tetraploidy‐selective suppression through the aggravation of spindle multipolarization. We also found that treatment with a CENP‐E inhibitor had superior generality to paclitaxel in its tetraploidy selectivity across a broader spectrum of cell lines. Our results highlight the unique properties of CENP‐E inhibitors in tetraploidy‐selective suppression and their potential use in the development of tetraploidy‐targeting interventions in cancer.

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Mammalian haploid somatic cells are unstable and prone to diploidize, but the cause of haploid instability remains largely unknown. Previously, we found that mammalian haploid somatic cells suffer chronic centrosome loss stemming from the uncoupling of DNA replication and centrosome duplication cycles. However, the lack of methodology to restore the coupling between DNA replication and centrosome duplication has precluded us from investigating the potential contribution of the haploidy-linked centrosome loss to haploid instability. In this study, we developed an experimental method that allows the re-coupling of DNA and centrosome cycles through the chronic extension of the G1/S phase without compromising cell proliferation using thymidine treatment/release cycles. Chronic extension of G1/S restored normal mitotic centrosome number and mitotic control, substantially improving the stability of the haploid state in HAP1 cells. Stabilization of the haploid state was compromised when cdk2 was inhibited during the extended G1/S, or when early G1 was chronically extended instead of G1/S, showing that the coupling of DNA and centrosome cycles rather than a general extension of the cell cycle is required for haploid stability. Our data indicate the chronic centriole loss arising from the uncoupling of centrosome and DNA cycles as a direct cause of genome instability in haploid somatic cells, and also demonstrate the feasibility of modulation of haploid stability through artificial coordination between DNA and centrosome cycles in mammalian somatic cells.

Tetraploidy caused by whole-genome duplication is a hallmark of cancer cells, and tetraploidy-selective cell growth suppression is a potential strategy for targeted cancer therapy. However, how tetraploid cells differ from normal diploids in their sensitivity to anti-proliferative treatments remains largely unknown. In this study, we found that tetraploid cells are significantly more susceptible to inhibitors of a mitotic kinesin CENP-E than diploids. CENP-E inhibitor preferentially diminished the tetraploid cell population in diploid-tetraploid co-culture at optimum conditions. Live imaging revealed that tetraploidy-linked increase in unsolvable polar chromosome misalignment caused substantially longer mitotic delay in tetraploids than in diploids upon moderate CENP-E inhibition. This time gap of mitotic arrest resulted in cohesion fatigue and subsequent cell death, specifically in tetraploids, leading to tetraploidy-selective cell growth suppression. In contrast, the microtubule-stabilizing compound paclitaxel caused tetraploidy-selective growth suppression through the aggravation of spindle multipolarization. We also found that CENP-E inhibitors had superior generality to paclitaxel in its tetraploidy selectivity across a broader spectrum of cell lines. Our results highlight the unique properties of CENP-E inhibitors in tetraploidy-selective suppression, giving us clues on the further development of tetraploidy-targeting interventions in cancer.

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The somatic haploidy is unstable in diplontic animals, but cellular processes determining haploid stability remain elusive. Here, we found that inhibition of mevalonate pathway by pitavastatin, a widely used cholesterol-lowering drug, drastically destabilized the haploid state in HAP1 cells. Interestingly, cholesterol supplementation did not restore haploid stability in pitavastatin-treated cells, and cholesterol inhibitor U18666A did not phenocopy haploid destabilization. These results ruled out the involvement of cholesterol in haploid stability. Besides cholesterol perturbation, pitavastatin induced endoplasmic reticulum (ER) stress, the suppression of which by a chemical chaperon significantly restored haploid stability in pitavastatin-treated cells. Our data demonstrate the involvement of the mevalonate pathway in the stability of the haploid state in human somatic cells through managing ER stress, highlighting a novel link between ploidy and ER homeostatic control.