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

doi:10.1083/JCB.202007195

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

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

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 language	English (US)
Article number	e202007195
Journal	Journal of Cell Biology
Volume	220
Issue number	4
DOIs	https://doi.org/10.1083/JCB.202007195
State	Published - Feb 2021

Funding

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. D.R. Foltz and A.K. Hogan were supported by National Institutes of Health grant R01GM111907 and a Zell Scholar award from the Robert H. Lurie Comprehensive Cancer Center. D. Fa-chinetti was supported by the Centre National de la Recherche Scientifique. C.L. Sanders, S. Difilippantonio, and B. Karim were funded by the National Institutes of Health, National Cancer Institute, under contract no. 75N91019D00024. The authors declare no competing financial interests.

ASJC Scopus subject areas

Cell Biology

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10.1083/JCB.202007195

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Shrestha, R. L., Rossi, A., Wangsa, D., Hogan, A. K., Zaldana, K. S., Suva, E., Chung, Y. J., Sanders, C. L., Difilippantonio, S., Karpova, T. S., Karim, B., Foltz, D. R., Fachinetti, D., Aplan, P. D., Ried, T., & Basrai, M. A. (2021). CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity. Journal of Cell Biology, 220(4), Article e202007195. https://doi.org/10.1083/JCB.202007195

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title = "CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity",

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.",

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

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year = "2021",

month = feb,

doi = "10.1083/JCB.202007195",

language = "English (US)",

volume = "220",

journal = "Journal of Cell Biology",

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AU - Shrestha, Roshan L.

AU - Rossi, Austin

AU - Wangsa, Darawalee

AU - Hogan, Ann K.

AU - Zaldana, Kimberly S.

AU - Suva, Evelyn

AU - Chung, Yang Jo

AU - Sanders, Chelsea L.

AU - Difilippantonio, Simone

AU - Karpova, Tatiana S.

AU - Karim, Baktiar

AU - Foltz, Daniel R.

AU - Fachinetti, Daniele

AU - Aplan, Peter D.

AU - Ried, Thomas

AU - Basrai, Munira A.

PY - 2021/2

Y1 - 2021/2

N2 - 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.

AB - 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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CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity

Abstract

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