CENPA a Genomic Marker for Centromere Activity and Human Diseases

Valdivia, Manuel M.; Hamdouch, Khaoula; Ortiz, Manuela; Astola, Antonio

doi:10.2174/138920209788920985

Cited by 35 publications

(26 citation statements)

References 111 publications

(162 reference statements)

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“…HJURP and CENPA interact for correctly loading new CENPA-containing nucleosomes on the centromere, thus ensuring fidelity during chromosome segregation [24,25]. Hu et al studied BCa cell lines and primary BCa cohorts and found that there was a statistically significant correlation between mRNA expression levels of HJURP and CENPA [27]. In vitro studies in BCa cell lines showed that RT led to increased apoptosis in cells with higher HJURP levels compared to cells with low HJURP expression levels; whereas using RNA interference studies (RNAi), it was shown that knocking down HJURP in human BCa cells led to decreased sensitivity to RT [26].…”

Section: Resultsmentioning

confidence: 99%

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Immunohistochemical Assessment of Expression of Centromere Protein—A (CENPA) in Human Invasive Breast Cancer

Rajput

Varma

et al. 2011

Cancers

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Abnormal cell division leading to the gain or loss of entire chromosomes and consequent genetic instability is a hallmark of cancer. Centromere protein –A (CENPA) is a centromere-specific histone-H3-like variant gene involved in regulating chromosome segregation during cell division. CENPA is one of the genes included in some of the commercially available RNA based prognostic assays for breast cancer (BCa)—the 70 gene signature MammaPrint® and the five gene Molecular Grade Index (MGISM). Our aim was to assess the immunohistochemical (IHC) expression of CENPA in normal and malignant breast tissue. Clinically annotated triplicate core tissue microarrays of 63 invasive BCa and 20 normal breast samples were stained with a monoclonal antibody against CENPA and scored for percentage of visibly stained nuclei. Survival analyses with Kaplan–Meier (KM) estimate and Cox proportional hazards regression models were applied to assess the associations between CENPA expression and disease free survival (DFS). Average percentage of nuclei visibly stained with CENPA antibody was significantly higher (p = 0.02) in BCa than normal tissue. The 3-year DFS in tumors over-expressing CENPA (>50% stained nuclei) was 79% compared to 85% in low expression tumors (<50% stained nuclei). On multivariate analysis, IHC expression of CENPA showed weak association with DFS (HR > 60.07; p = 0.06) within our small cohort. To the best of our knowledge, this is the first published report evaluating the implications of increased IHC expression of CENPA in paraffin embedded breast tissue samples. Our finding that increased CENPA expression may be associated with shorter DFS in BCa supports its exploration as a potential prognostic biomarker.

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Section: Resultsmentioning

confidence: 99%

“…Mis-localization of CENPA leading to genome instability has been suggested [27]. In colorectal cancer cells, CENPA over-expression has been shown to result in mistargeting of the protein to noncentromeric regions, thus depleting other centromere-kinetochore components and disrupting the kinetochore complex.…”

Section: Resultsmentioning

confidence: 99%

Immunohistochemical Assessment of Expression of Centromere Protein—A (CENPA) in Human Invasive Breast Cancer

Rajput

Varma

et al. 2011

Cancers

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“…CENP-A is required for the recruitment of centromeric proteins, proper kinetochore assembly, and chromosome segregation. After DNA replication and cytokinesis, CENP-A accumulates in the nucleosome region of replicated centromeres to maintain homeostasis between CENP-A protein levels and the epigenetic mechanism of chromatin assembly of the newly replicated centromeres (32, 33). If there is a defect in the completion of cytokinesis, then CENP-A will not accumulate in the nucleosome region of the newly replicated centromeres and will accumulate in the cytosol as free CENP-A protein.…”

Section: Discussionmentioning

confidence: 99%

Aurora A Kinase Inhibition Selectively Synergizes with Histone Deacetylase Inhibitor through Cytokinesis Failure in T-cell Lymphoma

Zullo

Guo

Cooke

et al. 2015

Clinical Cancer Research

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Purpose Aurora A kinase (AAK) is expressed exclusively during mitosis, and plays a critical role in centrosome duplication and spindle formation. Alisertib is a highly selective AAK inhibitor that has demonstrated marked clinical activity of alisertib across a spectrum of lymphomas, though particularly in patients with T-cell lymphoma (TCL). We sought to compare and contrast the activity of alisertib in preclinical models of B-cell lymphoma (BCL) and TCL, and identify combinations worthy of clinical study. High-throughput screening of pralatrexate, the proteasome inhibitor (ixazomib), and the histone deacetylase (HDAC) inhibitor (romidepsin) revealed that only romidepsin synergized with alisertib, and only in models of TCL. We discovered that the mechanism of synergy between AAK inhibitors and HDAC inhibitors appears to be mediated through cytokinesis failure. Experimental Design A high-throughput screening approach was used to identify drugs that were potentially synergistic in combination with alisertib. Live-cell imaging was used to explore the mechanistic basis for the drug: drug interaction between alisertib and romidepsin. An in vivo xenograft TCL model was used to confirm in vitro results. Results In vitro, alisertib exhibited concentration-dependent cytotoxicity in BCL and TCL cell lines. Alisertib was synergistic with romidepsin in a T-cell–specific fashion that was confirmed in vivo. Live-cell imaging demonstrated that the combination treatment resulted in profound cytokinesis failure. Conclusions These data strongly suggest that the combination of alisertib and romidepsin is highly synergistic in TCL through modulation of cytokinesis and merits clinical development.

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“…Human histone H3 has 6 different variants, among which CENP-A (CenH3, centromeric H3) is the most well known [51]. CENP-A plays a critical role to chromosome segregation via centromere association [42,52] – It replaces H3 at centromeres and is crucial to dictating centromeric positioning on chromosomes. The timing of CENP-A incorporation is critical as unscheduled CENP-A insertion disrupts kinetochore assembly and function [53].…”

Section: Architectural and Functional Components Of Chromatinmentioning

confidence: 99%

Genome maintenance in the context of 4D chromatin condensation

Yang

Shen

2016

Cell. Mol. Life Sci.

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The eukaryotic genome is packaged in the three-dimensional nuclear space by forming loops, domains and compartments in a hierarchical manner. However, when duplicated genomes prepare for segregation, mitotic cells eliminate topologically associating domains and abandon the compartmentalized structure. Alongside chromatin architecture reorganization during the transition from interphase to mitosis, cells halt most DNA-templated processes such as transcription and repair. The intrinsically condensed chromatin serves as a sophisticated signaling module subjected to selective relaxation for programmed genomic activities. To understand the elaborate genome-epigenome interplay during cell cycle progression, the steady three-dimensional genome requires a time scale to form a dynamic four-dimensional and a more comprehensive portrait. In this review, we will dissect the functions of critical chromatin architectural components in constructing and maintaining an orderly packaged chromatin environment. We will also highlight the importance of the spatially-and-temporally-conscious orchestration of chromatin remodeling to ensure high-fidelity genetic transmission.

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CENPA a Genomic Marker for Centromere Activity and Human Diseases

Cited by 35 publications

References 111 publications

Immunohistochemical Assessment of Expression of Centromere Protein—A (CENPA) in Human Invasive Breast Cancer

Immunohistochemical Assessment of Expression of Centromere Protein—A (CENPA) in Human Invasive Breast Cancer

Aurora A Kinase Inhibition Selectively Synergizes with Histone Deacetylase Inhibitor through Cytokinesis Failure in T-cell Lymphoma

Genome maintenance in the context of 4D chromatin condensation

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