Mevalonate Pathway-mediated ER Homeostasis Is Required for Haploid Stability in Human Somatic Cells

Cell Struct Funct. 2021 Feb 19;46(1):1-9. doi: 10.1247/csf.20055. Epub 2020 Dec 22.

Abstract

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.Key words: haploid, ER stress, Mevalonate pathway.

Keywords: ER stress; Mevalonate pathway; haploid.

MeSH terms

  • Cell Line
  • Cholesterol
  • Endoplasmic Reticulum Stress*
  • Haploidy
  • Homeostasis*
  • Humans

Substances

  • Cholesterol

Grants and funding

This work was supported by JSPS KAKENHI (Grant #19J12210 to K.Ya., 19H03219, 19H05413, and 19KK0181 to R.U), the Hungarian National Research, Development and Innovation Office (NKFIH grant #FK124442) and János Bolyai Research Scholarship from HAS to E.M., the Princess Takamatsu Cancer Research Fund, the Kato Memorial Bioscience Foundation, the Orange Foundation, the Smoking Research Foundation, the Suhara Memorial Foundation, and the Nakatani Foundation to R.U., and Bilateral Joint Research Projects of JSPS and HAS (JPJSBP120193801) to G.B., E.M., and R.U.