CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity

Roshan L. Shrestha, Austin Rossi, Darawalee Wangsa, Ann K. Hogan, Kimberly S. Zaldana, Evelyn Suva, Yang Jo Chung, Chelsea L. Sanders, Simone Difilippantonio, Tatiana S. Karpova, Baktiar Karim, Daniel R. Foltz, Daniele Fachinetti, Peter D. Aplan, Thomas Ried, Munira A. Basrai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Chromosomal instability (CIN) is a hallmark of many cancers. Restricting the localization of centromeric histone H3 variant CENP-A to centromeres prevents CIN. CENP-A overexpression (OE) and mislocalization have been observed in cancers and correlate with poor prognosis; however, the molecular consequences of CENP-A OE on CIN and aneuploidy have not been defined. Here, we show that CENP-A OE leads to its mislocalization and CIN with lagging chromosomes and micronuclei in pseudodiploid DLD1 cells and xenograft mouse model. CIN is due to reduced localization of proteins to the kinetochore, resulting in defects in kinetochore integrity and unstable kinetochore–microtubule attachments. CENP-A OE contributes to reduced expression of cell adhesion genes and higher invasion of DLD1 cells. We show that CENP-A OE contributes to aneuploidy with karyotypic heterogeneity in human cells and xenograft mouse model. In summary, our results provide a molecular link between CENP-A OE and aneuploidy, and suggest that karyotypic heterogeneity may contribute to the aggressive phenotype of CENP-A–overexpressing cancers.

Original languageEnglish (US)
Article numbere202007195
JournalJournal of Cell Biology
Volume220
Issue number4
DOIs
StatePublished - Feb 2021

ASJC Scopus subject areas

  • Cell Biology

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