CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity

Author:

Shrestha, Roshan L.

Rossi, Austin

Wangsa, Darawalee

Hogan, Ann K.

Zaldana, Kimberly S.

Suva, Evelyn

Chung, Yang Jo

Sanders,Chelsea

Difilippantonio,Simone

Karpova, Tatiana S.

Karim,Baktiar

Foltz, Daniel R.

Fachinetti, Daniele

Aplan, Peter D.

Ried, Thomas

Basrai, Munira A.
Author Address

NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.Frederick Natl Lab Canc Res, Lab Anim Sci Program, Leidos Biomed Res, Frederick, MD USA.Northwestern Univ, Dept Biochem & Mol Genet, Chicago, IL 60611 USA.NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.PSL Res Univ, CNRS, Inst Curie, Unite Mixte Rech 144, Paris, France.

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.

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