Antioxidant treatment ameliorates phenotypic features of SMC1A-mutated Cornelia de Lange syndrome in vitro and in vivo

Cukrov, Dubravka; Newman, Trent; Leask, Megan; Leeke, Bryony; Sarogni, Patrizia; Patimo, Alessandra; Kline, Antonie D.; Krantz, Ian D.; Horsfield, Julia A.; Musio, Antonio

doi:10.1093/hmg/ddy203

Cited by 30 publications

(31 citation statements)

References 61 publications

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“…This mode of glycolysis is similar to that observed in cancer cells and is known as the Warburg effect [78,79]. Metabolic and oxidative stress disturbances in cohesin mutant cells observed in this study and others [38,80] might similarly influence -catenin stability and in turn, sensitivity to incoming Wnt signals. mutations c.2027A>G and c.2479 C>T was described previously [54].…”

Section: Discussionsupporting

confidence: 85%

Cohesin mutations are synthetic lethal with stimulation of WNT signaling

Chin

Antony

Ketharnathan

et al. 2020

eLife

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Mutations in genes encoding subunits of the cohesin complex are common in several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations of genes encoding cohesin subunits SMC3, RAD21, and STAG2 and screened for synthetic lethality with 3009 FDA-approved compounds. The screen identified several compounds that interfere with transcription, DNA damage repair and the cell cycle. Unexpectedly, one of the top ‘hits’ was a GSK3 inhibitor, an agonist of Wnt signaling. We show that sensitivity to GSK3 inhibition is likely due to stabilization of β-catenin in cohesin-mutant cells, and that Wnt-responsive gene expression is highly sensitized in STAG2-mutant CMK leukemia cells. Moreover, Wnt activity is enhanced in zebrafish mutant for cohesin subunits stag2b and rad21. Our results suggest that cohesin mutations could progress oncogenesis by enhancing Wnt signaling, and that targeting the Wnt pathway may represent a novel therapeutic strategy for cohesin-mutant cancers.

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Section: Discussionsupporting

confidence: 85%

Cohesin mutations are synthetic lethal with stimulation of WNT signaling

Chin

Antony

Ketharnathan

et al. 2020

eLife

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“…Treatment with antioxidant drugs reduces both the level of oxidative stress and genome instability, leading to the extension of in vitro lifespan of CdLS cell lines. In addition, treatment ameliorates the phenotypic feature of zebrafish modelling of CdLS 92. Antioxidant drugs protect the DNA from damage and prevent cell death, as shown in cerebellar cells using N -acetyl-cysteine 112 113.…”

Section: Introductionmentioning

confidence: 99%

“…CdLS cells are characterised by genome instability, as evidenced by the presence of chromosomal rearrangements and aberrations such as translocations, deletions, gaps and breaks 48 49 72 92. In addition, cells are sensitive to genotoxic drugs such as aphidicolin and mytomicin C, and X-ray exposure,72 93 suggesting that CdLS cells have a reduced ability to tolerate DNA damage, likely as a result of reduced DNA repair capability.…”

Section: Introductionmentioning

confidence: 99%

Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach

2019

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Cornelia de Lange syndrome (CdLS) is a severe genetic disorder characterised by multisystemic malformations. CdLS is due to pathogenetic variants in NIPBL, SMC1A, SMC3, RAD21 and HDAC8 genes which belong to the cohesin pathway. Cohesin plays a pivotal role in chromatid cohesion, gene expression, and DNA repair. In this review, we will discuss how perturbations in those biological processes contribute to CdLS phenotype and will emphasise the state-of-art of CdLS therapeutic approaches.

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“…Germline mutations in cohesin and its regulators are responsible for Cornelia de Lange syndrome (CdLS) [18–23], a rare developmental disease characterized by both chromosome aneuploidies and aberrations, precocious sister chromatid separation and sensitivity to genotoxic drugs [24–27]. Despite these considerations, CdLS patients do not show predisposition to cancer [26].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development

Sarogni

Palumbo

Servadio

et al. 2019

J Exp Clin Cancer Res

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Background Cancer cells are characterized by chromosomal instability (CIN) and it is thought that errors in pathways involved in faithful chromosome segregation play a pivotal role in the genesis of CIN. Cohesin forms a large protein ring that binds DNA strands by encircling them. In addition to this central role in chromosome segregation, cohesin is also needed for DNA repair, gene transcription regulation and chromatin architecture. Though mutations in both cohesin and cohesin-regulator genes have been identified in many human cancers, the contribution of cohesin to cancer development is still under debate. Methods Normal mucosa, early adenoma, and carcinoma samples deriving from 16 subjects affected by colorectal cancer (CRC) were analyzed by OncoScan for scoring both chromosome gains and losses (CNVs) and loss of heterozygosity (LOH). Then the expression of SMC1A was analyzed by immunochemistry in 66 subjects affected by CRC. The effects of SMC1A overexpression and mutated SMC1A were analyzed in vivo using immunocompromised mouse models. Finally, we measured global gene expression profiles in induced-tumors by RNA-seq. Results Here we showed that SMC1A cohesin core gene was present as extra-copies, mutated, and overexpressed in human colorectal carcinomas. We then demonstrated that cohesin overexpression led to the development of aggressive cancers in immunocompromised mice through gene expression dysregulation. Conclusion Collectively, these results support a role of defective cohesin in the development of human colorectal cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1116-0) contains supplementary material, which is available to authorized users.

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Antioxidant treatment ameliorates phenotypic features of SMC1A-mutated Cornelia de Lange syndrome in vitro and in vivo

Cited by 30 publications

References 61 publications

Cohesin mutations are synthetic lethal with stimulation of WNT signaling

Cohesin mutations are synthetic lethal with stimulation of WNT signaling

Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach

Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development

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