Subunits of human condensins are potential therapeutic targets for cancers

Wang, Hong-Zhen; Yang, Sihan; Li, Guiying; Cao, Xudong

doi:10.1186/s13008-018-0035-3

Cited by 19 publications

(20 citation statements)

References 105 publications

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“…9B ). The condensin complex has been suggested as a potential therapeutic target for cancer [138], and human homologs YCG1/NCAPG2 , YCS4/NCAPD2 , and SMC4/SMC4 are synthetic lethal with the Ras oncogene [124].…”

Section: Resultsmentioning

confidence: 99%

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A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

Santos

Hartman

2019

Preprint

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Background: Saccharomyces cerevisiae represses respiration in the presence of adequate glucose, mimicking the Warburg effect, termed aerobic glycolysis. We conducted yeast phenomic experiments to characterize differential doxorubicin-gene interaction, in the context of respiration vs. glycolysis. The resulting systems level biology about doxorubicin cytotoxicity, including the influence of the Warburg effect, was integrated with cancer pharmacogenomics data to identify potentially causal correlations between differential gene expression and anti-cancer efficacy. Methods: Quantitative high-throughput cell array phenotyping (Q-HTCP) was used to measure cell proliferation phenotypes (CPPs) of the yeast gene knockout/knockdown library, treated with escalating doxorubicin concentrations in fermentable and non-fermentable media. Doxorubicin-gene interaction was quantified by departure of the observed and expected phenotypes for the doxorubicin-treated mutant strain, with respect to phenotypes for the untreated mutant strain and both the treated and untreated reference strain. Recursive expectation-maximization clustering (REMc) and Gene Ontology-based analyses of interactions were used to identify functional biological modules that buffer doxorubicin cytotoxicity, and to characterize their Warburg-dependence. Yeast phenomic data was applied to cancer cell line pharmacogenomics data to predict differential gene expression that causally influences the anti-tumor efficacy, and potentially the anthracycline-associated host toxicity, of doxorubicin. Results: Doxorubicin cytotoxicity was greater with respiration, suggesting the Warburg effect can influence therapeutic efficacy. Accordingly, doxorubicin drug-gene interaction was more extensive with respiration, including increased buffering by cellular processes related to chromatin organization, protein folding and modification, translation reinitiation, spermine metabolism, and fatty acid beta-oxidation. Pathway enrichment was less notable for glycolysis-specific buffering. Cellular processes exerting influence relatively independently, with respect to Warburg status, included homologous recombination, sphingolipid homeostasis, telomere tethering at nuclear periphery, and actin cortical patch localization. Causality for differential gene expression associated with doxorubicin cytotoxicity in tumor cells was predicted within the biological context of the phenomic model. Conclusions: Warburg status influences the genetic requirements to buffer doxorubicin toxicity. Yeast phenomics provides an experimental platform to model the complexity of gene interaction networks that influence human disease phenotypes, as in this example of chemotherapy response. High-resolution, systems level yeast phenotyping is useful to predict the biological influence of functional variation on disease, offering the potential to fundamentally advance precision medicine.

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Section: Resultsmentioning

confidence: 99%

“…TMA22/DENR also exerts evolutionarily conserved influence on telomeric function and cell proliferation [215]. YCG1/NCAPG and SMC2/SMC2 are components of the condensin complex, which are overexpressed in cancer [138]. NUP170/NUP155 , which functions in telomere tethering at the nuclear periphery ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

Santos

Hartman

2019

Preprint

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“…Defective mitotic chromosome assembly is clinically relevant. Dysregulation of condensin complex I and II are both associated with poor prognosis and are gaining attention as potential therapeutic targets (Wang, Yang, Li, & Cao, 2018). High nCAP-D2 expression is associated with increased metastasis and decreased survival in triple negative breast cancer (Y.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor Sp1 regulates mitotic fidelity through Aurora B kinase-mediated condensin I localization

Flashner

Swift

Sowash

et al. 2020

Preprint

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Mitotic chromosome assembly is essential for faithful chromosome segregation. Despite their salient role directing interphase chromatin organization, little is known about how transcription factors mediate this process during mitosis. Here, we characterize a mitosis-specific role for transcription factor specificity protein 1 (Sp1). Sp1 localizes to mitotic centromeres and auxininduced rapid Sp1 degradation results in chromosome segregation errors and aberrant mitotic progression. These defects are driven by anomalous mitotic chromosome assembly. Sp1 degradation results in chromosome condensation defects through reduced condensin complex I localization. Sp1 also mediates the localization and activation of Aurora B kinase early in mitosis, which is essential for condensin complex I recruitment. Underscoring the clinical significance of our findings, aberrant Sp1 expression correlates with aneuploidy in several human cancers, including kidney renal papillary cell carcinoma, ovarian serous cystadenocarcinoma, mesothelioma, cholangiocarcinoma, and hepatocellular carcinoma. Our results suggest that Sp1 protects genomic integrity during mitosis by promoting chromosome assembly.

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“…One defect in subunits of condensin causes incomplete chromosome condensation . Thus, condensins could be a therapeutic target for human cancers . A recent report showed that NCAPH is upregulated in colon cancer tissue, and its high expression correlates with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…31 Thus, condensins could be a therapeutic target for human cancers. 32 A recent report showed that NCAPH is upregulated in colon cancer tissue, and its high expression correlates with poor prognosis. Furthermore, inhibiting NCAPH promotes cell apoptosis and cell cycle arrest at the G2/M phase, and exerts antitumor effects in colorectal cancer in vitro and in vivo.…”

Section: Chka Cdc6 Ncaphmentioning

confidence: 99%

Micro‐ribonucleic acid expression signature of metastatic castration‐resistant prostate cancer: Regulation of NCAPH by antitumor miR‐199a/b‐3p

et al. 2019

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Objectives To identify oncogenes regulated by micro‐ribonucleic acid, miR‐199a/b‐3p, in metastatic castration‐resistant prostate cancer. Methods Advanced ribonucleic acid sequencing technologies were applied to construct a micro‐ribonucleic acid expression signature using metastatic castration‐resistant prostate cancer autopsy specimens. Ectopic expression of mature micro‐ribonucleic acids or small‐interfering ribonucleic acids were applied to functional assays for cancer cell lines. Genome‐wide gene expression and in silico database analyses were carried out to predict micro‐ribonucleic acid targets. Results Ectopic expression of miR‐199a/b inhibited cancer cell aggressiveness. The gene coding for non‐structural maintenance of chromosomes condensin I complex subunit H was directly regulated by miR‐199a/b‐3p. High expression of condensin I complex subunit H was significantly associated with poor disease‐free survival by The Cancer Genome Atlas database analysis (P < 0.0001). Overexpression of condensin I complex subunit H was detected in hormone‐sensitive prostate cancer and castration‐resistant prostate cancer specimens, and knockdown assays showed that its expression enhanced cancer cell migration and invasive abilities. Conclusions Small ribonucleic acid sequencing of metastatic castration‐resistant prostate cancer specimens showed the presence of several antitumor micro‐ribonucleic acids whose targets are involved in hormone‐sensitive prostate cancer and metastatic castration‐resistant prostate cancer pathogenesis. Condensin I complex subunit H seems to be a promising diagnostic marker and therapeutic target for this disease. Our approach, based on the roles of anti‐tumor micro‐ribonucleic acids and their targets, will contribute to an improved understanding of the molecular pathogenesis of hormone‐sensitive prostate cancer and metastatic castration‐resistant prostate cancer.

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Subunits of human condensins are potential therapeutic targets for cancers

Cited by 19 publications

References 105 publications

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

Transcription factor Sp1 regulates mitotic fidelity through Aurora B kinase-mediated condensin I localization

Micro‐ribonucleic acid expression signature of metastatic castration‐resistant prostate cancer: Regulation of NCAPH by antitumor miR‐199a/b‐3p

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