Sustained chromosomal passenger complex activity preserves the pluripotency of human embryonic carcinoma cells

  • Sci Signal. 2025 Feb 18;18(874):eadg4626. doi: 10.1126/scisignal.adg4626.
Takaaki Tsunematsu  1 ,  Yasuhiro Mouri  2 ,  Wenhua Shao  2 ,  Rieko Arakaki  1 ,  Jan G Ruppert  3 ,  Kensaku Murano  4 ,  Naozumi Ishimaru  1 ,  Daniele Guardavaccaro  5 ,  Michele Pagano  6  7  8 ,  Yasusei Kudo  2
Affiliations
  • 1. Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan.
  • 2. Department of Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan.
  • 3. Wellcome Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, Scotland, UK.
  • 4. Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan.
  • 5. Department of Biotechnology, University of Verona, 37134 Verona, Italy.
  • 6. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
  • 7. NYU Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
  • 8. Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
PMID: 40136047 DOI: 10.1126/scisignal.adg4626
Abstract

Human embryonic carcinoma (hEC) cells are derived from teratocarcinomas, exhibit robust proliferation, have a high differentiation potential, are the malignant counterparts of human embryonic stem cells (hESCs), and are considered hESC-like. The chromosomal passenger complex (CPC), made up of the microtuble binding protein Borealin, the kinase Aurora-B, the CPC-stabilizing inner centromere protein (INCENP), and the inhibitor of Apoptosis family member Survivin, regulates cell division and is active exclusively during Mitosis in somatic cells. The anaphase-promoting complex/cyclosome and its cofactor Cdh1 (APC/CCdh1) is a ubiquitylating complex that catalyzes the degradation of Aurora-B and Borealin in somatic cells but has low activity during interphase in hESCs. Here, we found that Borealin and Aurora-B exhibited sustained stability throughout the cell cycle of hEC cells due to low APC/CCdh1 activity. In contrast with somatic cells, CPC activity persisted across the cell cycle of hEC cells because of diminished APC/CCdh1 activity. Disrupting the CPC complex by depleting its constituents triggered spontaneous differentiation in hEC cells. As hEC cells differentiated, APC/CCdh1 activation curtailed CPC activity. Inactivating the CPC by pharmacologically inhibiting Aurora-B induced hEC cell differentiation by activating the epithelial-to-mesenchymal transition (EMT) program. Hence, APC/CCdh1-mediated termination of CPC activity triggered hEC cell differentiation. Collectively, these findings demonstrate a role for the CPC in governing hESC cell fate.

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