scholarly journals CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity

2021 ◽  
Vol 220 (4) ◽  
Author(s):  
Roshan L. Shrestha ◽  
Austin Rossi ◽  
Darawalee Wangsa ◽  
Ann K. Hogan ◽  
Kimberly S. Zaldana ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Mouse Model ◽  
Chromosomal Instability ◽  
Poor Prognosis ◽  
Histone H3 ◽  
Human Cells ◽  
Xenograft Mouse Model ◽  
Aggressive Phenotype ◽  
Histone H3 Variant

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.

scholarly journals Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells

Oncotarget ◽  
2017 ◽  
Vol 8 (29) ◽  
pp. 46781-46800 ◽  
Author(s):  
Roshan L. Shrestha ◽  
Grace S. Ahn ◽  
Mae I. Staples ◽  
Kizhakke M. Sathyan ◽  
Tatiana S. Karpova ◽  
...  
Keyword(s):  
Chromosomal Instability ◽  
Histone H3 ◽  
Human Cells ◽  
Histone H3 Variant

scholarly journals Reduced Gene Dosage of Histone H4 Prevents CENP-A Mislocalization and Chromosomal Instability in Saccharomyces cerevisiae

Genetics ◽  
2021 ◽  
Author(s):  
Jessica R Eisenstatt ◽  
Kentaro Ohkuni ◽  
Wei-Chun Au ◽  
Olivia Preston ◽  
Loran Gliford ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Chromosomal Instability ◽  
Budding Yeast ◽  
Gene Dosage ◽  
Histone H3 ◽  
Human Cells ◽  
Histone H4 ◽  
Genome Wide ◽  
A Genome ◽  
Histone H3 Variant

Abstract Mislocalization of the centromeric histone H3 variant (Cse4 in budding yeast, CID in flies, CENP-A in humans) to non-centromeric regions contributes to chromosomal instability (CIN) in yeast, fly, and human cells. Overexpression and mislocalization of CENP-A has been observed in cancers, however, the mechanisms that facilitate the mislocalization of overexpressed CENP-A have not been fully explored. Defects in proteolysis of overexpressed Cse4 (GALCSE4) leads to its mislocalization and synthetic dosage lethality (SDL) in mutants for E3 ubiquitin ligases (Psh1, Slx5, SCFMet30, SCFCdc4), Doa1, Hir2, and Cdc7. In contrast, defects in sumoylation of overexpressed cse4K215/216/A/R prevent its mislocalization and do not cause SDL in a psh1Δ strain. Here, we used a genome-wide screen to identify factors that facilitate the mislocalization of overexpressed Cse4 by characterizing suppressors of the psh1Δ GALCSE4 SDL. Deletions of histone H4 alleles (HHF1 or HHF2), which were among the most prominent suppressors, also suppress slx5Δ, cdc4-1, doa1Δ, hir2Δ, and cdc7-4 GALCSE4 SDL. Reduced dosage of H4 leads to defects in sumoylation and reduced mislocalization of overexpressed Cse4, which contributes to suppression of CIN when Cse4 is overexpressed. We determined that the hhf1-20, cse4-102, and cse4-111 mutants, which are defective in the Cse4-H4 interaction, also exhibit reduced sumoylation of Cse4 and do not display psh1Δ GALCSE4 SDL. In summary, we have identified genes that contribute to the mislocalization of overexpressed Cse4 and defined a role for the gene dosage of H4 in facilitating Cse4 sumoylation and mislocalization to non-centromeric regions, leading to CIN when Cse4 is overexpressed.

scholarly journals Distinct chromatin signature of histone H3 variant H3.3 in human cells

Nucleus ◽  
2014 ◽  
Vol 5 (5) ◽  
pp. 449-461 ◽  
Author(s):  
Luc Snyers ◽  
Gordin Zupkovitz ◽  
Marlene Almeder ◽  
Marianne Fliesser ◽  
Anja Stoisser ◽  
...  
Keyword(s):  
Histone H3 ◽  
Human Cells ◽  
Chromatin Signature ◽  
Histone H3 Variant

scholarly journals Reduced Gene Dosage of Histone H4 Prevents CENP-A Mislocalization in Saccharomyces cerevisiae

2020 ◽  
Author(s):  
Jessica R. Eisenstatt ◽  
Kentaro Ohkuni ◽  
Wei-Chun Au ◽  
Olivia Preston ◽  
Evelyn Suva ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Chromosomal Instability ◽  
Budding Yeast ◽  
Gene Dosage ◽  
Histone H3 ◽  
Histone H4 ◽  
Genome Wide ◽  
A Genome ◽  
Mutant Strains ◽  
Histone H3 Variant

ABSTRACTMislocalization of the centromeric histone H3 variant (Cse4 in budding yeast, CID in flies, CENP-A in humans) to non-centromeric regions contributes to chromosomal instability (CIN) in yeast, fly, and human cells. Overexpression and mislocalization of CENP-A has been observed in cancers, however, the mechanisms that facilitate the mislocalization of overexpressed CENP-A have not been fully explored. Defects in ubiquitin-mediated proteolysis of overexpressed Cse4 (GALCSE4) leads to its mislocalization and synthetic dosage lethality (SDL) in mutants for E3 ubiquitin ligases (Psh1, Slx5, SCFMet30, SCFCdc4), Doa1, Hir2, and Cdc7. In contrast, defects in sumoylation of GALcse4K215/216/A/R prevent its mislocalization and do not cause SDL in a psh1Δ strain. Here, we used a genome-wide screen to identify factors that facilitate the mislocalization of overexpressed Cse4 by characterizing suppressors of the psh1Δ GALCSE4 SDL. Deletions of histone H4 alleles (HHF1 or HHF2), which were among the most prominent suppressors, also suppress slx5Δ, cdc4-1, doa1Δ, hir2Δ, and cdc7-4 GALCSE4 SDL. Reduced dosage of H4 contributes to defects in sumoylation and reduced mislocalization of overexpressed Cse4. We determined that the hhf1-20, cse4-102, and cse4-111 mutants, which are defective in the Cse4-H4 interaction, also exhibit reduced sumoylation of Cse4 and do not display psh1Δ GALCSE4 SDL. In summary, we have identified genes that contribute to the mislocalization of overexpressed Cse4 and defined a role for the gene dosage of H4 in facilitating Cse4 sumoylation and mislocalization to non-centromeric regions, contributing to SDL when Cse4 is overexpressed in mutant strains.

scholarly journals BEX1 and BEX4 Induce GBM Progression through Regulation of Actin Polymerization and Activation of YAP/TAZ Signaling

2021 ◽  
Vol 22 (18) ◽  
pp. 9845
Author(s):  
Sungmin Lee ◽  
Hyunkoo Kang ◽  
Eunguk Shin ◽  
Jaewan Jeon ◽  
HyeSook Youn ◽  
...  
Keyword(s):  
Mouse Model ◽  
Glial Cells ◽  
Poor Prognosis ◽  
Actin Polymerization ◽  
Tumor Formation ◽  
High Grade ◽  
Latrunculin B ◽  
Xenograft Mouse Model ◽  
Orthotopic Xenograft ◽  
Radiation Induced

GBM is a high-grade cancer that originates from glial cells and has a poor prognosis. Although a combination of surgery, radiotherapy, and chemotherapy is prescribed to patients, GBM is highly resistant to therapies, and surviving cells show increased aggressiveness. In this study, we investigated the molecular mechanism underlying GBM progression after radiotherapy by establishing a GBM orthotopic xenograft mouse model. Based on transcriptomic analysis, we found that the expression of BEX1 and BEX4 was upregulated in GBM cells surviving radiotherapy. We also found that upregulated expression of BEX1 and BEX4 was involved in the formation of the filamentous cytoskeleton and altered mechanotransduction, which resulted in the activation of the YAP/TAZ signaling pathway. BEX1- and BEX4-mediated YAP/TAZ activation enhanced the tumor formation, growth, and radioresistance of GBM cells. Additionally, latrunculin B inhibited GBM progression after radiotherapy by suppressing actin polymerization in an orthotopic xenograft mouse model. Taken together, we suggest the involvement of cytoskeleton formation in radiation-induced GBM progression and latrunculin B as a GBM radiosensitizer.

scholarly journals Force estimation from 4D OCT data in a human tumor xenograft mouse model

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Maximilian Neidhardt ◽  
Nils Gessert ◽  
Tobias Gosau ◽  
Julia Kemmling ◽  
Susanne Feldhaus ◽  
...  
Keyword(s):  
Deep Learning ◽  
Mouse Model ◽  
Haptic Feedback ◽  
Human Tumor ◽  
Tumor Xenograft ◽  
Human Tumor Xenograft ◽  
Force Estimation ◽  
Xenograft Mouse Model ◽  
Dead Tissue

AbstractMinimally invasive robotic surgery offer benefits such as reduced physical trauma, faster recovery and lesser pain for the patient. For these procedures, visual and haptic feedback to the surgeon is crucial when operating surgical tools without line-of-sight with a robot. External force sensors are biased by friction at the tool shaft and thereby cannot estimate forces between tool tip and tissue. As an alternative, vision-based force estimation was proposed. Here, interaction forces are directly learned from deformation observed by an external imaging system. Recently, an approach based on optical coherence tomography and deep learning has shown promising results. However, most experiments are performed on ex-vivo tissue. In this work, we demonstrate that models trained on dead tissue do not perform well in in vivo data. We performed multiple experiments on a human tumor xenograft mouse model, both on in vivo, perfused tissue and dead tissue. We compared two deep learning models in different training scenarios. Training on perfused, in vivo data improved model performance by 24% for in vivo force estimation.

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