STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma

Surdez, Didier; Zaïdi, Sakina; Grossetête, Sandrine; Laud-Duval, Karine; Ferre, Anna Sole; Mous, Lieke; Vourc’h, Thomas; Tirode, Franck; Pierron, Gaëlle; Raynal, Virginie; Baulande, Sylvain; Brunet, Erika; Hill, Véronique; Delattre, Olivier

doi:10.1016/j.ccell.2021.04.001

Cited by 63 publications

(60 citation statements)

References 109 publications

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“…In epithelial cancer cells, RAD21 depletion alters chromosome interactions around TGFB1 and ITGA5, leading to their activation and epithelial to mesenchymal transition [127]. STAG2 knockout in Ewing sarcoma cell lines was found to downregulate EWSR1-FLI1-anchored chromatin interactions and enhance the migratory potential of these cells [138]. Together these studies show that cohesin insufficiency can result in diverse aberrant cellular phenotypes.…”

Section: Cohesin In Cancermentioning

confidence: 85%

Cohesin Mutations in Cancer: Emerging Therapeutic Targets

Antony

Chin

Horsfield

2021

IJMS

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The cohesin complex is crucial for mediating sister chromatid cohesion and for hierarchal three-dimensional organization of the genome. Mutations in cohesin genes are present in a range of cancers. Extensive research over the last few years has shown that cohesin mutations are key events that contribute to neoplastic transformation. Cohesin is involved in a range of cellular processes; therefore, the impact of cohesin mutations in cancer is complex and can be cell context dependent. Candidate targets with therapeutic potential in cohesin mutant cells are emerging from functional studies. Here, we review emerging targets and pharmacological agents that have therapeutic potential in cohesin mutant cells.

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Section: Cohesin In Cancermentioning

confidence: 85%

Cohesin Mutations in Cancer: Emerging Therapeutic Targets

Antony

Chin

Horsfield

2021

IJMS

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“…In vertebrate somatic cells, there are two types of cohesin subunit protein, SA1 and SA2 (encoded by STAG1 and STAG2 genes), which hold SMC3, SMC1, and RAD21 proteins to form the cohesin protein complex, called cohesin-STAG1 and cohesin-STAG2 [ 218 ]. STAG2 is the most frequently mutated in solid cancers [ 219 , 220 ], and in hematologic malignancies, genes including STAG1 , STAG2 , RAD21 , SMC1A , and SMC3 are frequently mutated [ 221 – 223 ]. Also, precocious dissociation of sisters 5 (PDS5) is an associated protein of cohesin complex [ 224 ].…”

Section: Key Structural Elements Mediating 3d Chromatin Interactionsmentioning

confidence: 99%

3D chromatin architecture and transcription regulation in cancer

2022

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Chromatin has distinct three-dimensional (3D) architectures important in key biological processes, such as cell cycle, replication, differentiation, and transcription regulation. In turn, aberrant 3D structures play a vital role in developing abnormalities and diseases such as cancer. This review discusses key 3D chromatin structures (topologically associating domain, lamina-associated domain, and enhancer–promoter interactions) and corresponding structural protein elements mediating 3D chromatin interactions [CCCTC-binding factor, polycomb group protein, cohesin, and Brother of the Regulator of Imprinted Sites (BORIS) protein] with a highlight of their associations with cancer. We also summarise the recent development of technologies and bioinformatics approaches to study the 3D chromatin interactions in gene expression regulation, including crosslinking and proximity ligation methods in the bulk cell population (ChIA-PET and HiChIP) or single-molecule resolution (ChIA-drop), and methods other than proximity ligation, such as GAM, SPRITE, and super-resolution microscopy techniques.

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“…It has been suggested that STAG2 LOF increases the chance that mutated cells acquire tumor-driving mutations by extending cell life span [ 146 ]. This notion is supported by the observation that transcription factors ( MYC , NF-κB ) or signaling pathways (epithelial-to-mesenchymal transition, TGF-β , and EGF ) are impacted upon STAG2 LOF suggesting that these alterations may contribute to tumorigenesis [ 147 ].…”

Section: Effects Of Cohesin Dysfunction In Cancermentioning

confidence: 99%

The multifaceted roles of cohesin in cancer

Nardo

Pallotta

Musio

2022

J Exp Clin Cancer Res

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The cohesin complex controls faithful chromosome segregation by pairing sister chromatids after DNA replication until mitosis. In addition, it is crucial for hierarchal three-dimensional organization of the genome, transcription regulation and maintaining DNA integrity. The core complex subunits SMC1A, SMC3, STAG1/2, and RAD21 as well as its modulators, have been found to be recurrently mutated in human cancers. The mechanisms by which cohesin mutations trigger cancer development and disease progression are still poorly understood. Since cohesin is involved in a range of chromosome-related processes, the outcome of cohesin mutations in cancer is complex. Herein, we discuss recent discoveries regarding cohesin that provide new insight into its role in tumorigenesis.

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STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma

Cited by 63 publications

References 109 publications

Cohesin Mutations in Cancer: Emerging Therapeutic Targets

Cohesin Mutations in Cancer: Emerging Therapeutic Targets

3D chromatin architecture and transcription regulation in cancer

The multifaceted roles of cohesin in cancer

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