Journal
CANCER CELL
Volume 39, Issue 6, Pages 810-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2021.04.001
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Funding
- Institut Curie: the INSERM
- Canceropole Ile-de-France
- Ligue Nationale Contre le Cancer (Equipe labellisee)
- projet de Recherche Enfants, Adolescents et Cancer''
- Institut National du Cancer [PLBIO16-291]
- Fondation ARC
- Agence Nationale de la Recherche [ANR-10-EQPX-03]
- Institut Curie Genomique d'Excellence (ICGex)
- Societe Francaise de lutte contre les Cancers et les leucemies de l'Enfant et de l'adolescent (SFCE)
- European funding: ERA-NET TRANSCAN JTC-2011 [01KT1310]
- European funding: ERA-NET TRANSCAN JTC 2014 [TRAN201501238]
- European funding: TRANSCAN JTC 2017 [TRANS201801292]
- European funding: EEC [HEALTH-F2-2013-602856]
- European funding: H2020lMI2-JTl-201 5-07 [116064-ITCC P4]
- European funding: H2020-SC1-DTH-2018-1 [SEP-210 506374-iPC]
- Institut Curie-SIRIC (Site de Recherche Integree en Cancerologie) program
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The study reveals that STAG2-LOF fine-tunes the activity of an oncogenic transcription factor by altering anchored CTCF loop extrusion and enhancer mechanisms, thereby affecting the invasive behavior of Ewing sarcoma cells.
STAG2, a cohesin family gene, is among the most recurrently mutated genes in cancer. STAG2 loss of function (LOF) is associated with aggressive behavior in Ewing sarcoma, a childhood cancer driven by aberrant transcription induced by the EWSR1-FLI1 fusion oncogene. Here, using isogenic Ewing cells, we show that, while STAG2 LOF profoundly changes the transcriptome, it does not significantly impact EWSR1-FLI1, CTCF/cohesin, or acetylated H3K27 DNA binding patterns. In contrast, it strongly alters the anchored dynamic loop extrusion process at boundary CTCF sites and dramatically decreases promoter-enhancer interactions, particularly affecting the expression of genes regulated by EWSR1-FLI1 at GGAA microsatellite neo-enhancers. Down-modulation of cis-mediated EWSR1-FLI1 activity, observed in STAG2-LOF conditions, is associated with enhanced migration and invasion properties of Ewing cells previously observed in EWSR1-FLI1low cells. Our study illuminates a process whereby STAG2-LOF fine-tunes the activity of an oncogenic transcription factor through altered CTCF-anchored loop extrusion and cis-mediated enhancer mechanisms.
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