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STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma

Biniam Adane1, Gabriela Alexe2, Bo Kyung A Seong1

  • 1Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Cancer Cell
|June 15, 2021
PubMed

Insights

Mutations in the STAG2 gene disrupt chromatin structure and gene regulation in Ewing sarcoma. Loss of STAG2 promotes cancer cell migration and metastasis, highlighting its role in aggressive cancer.

Area of Science:

  • Molecular Biology
  • Cancer Genetics
  • Chromatin Biology

Background:

  • The core cohesin subunit STAG2 is frequently mutated in Ewing sarcoma.
  • The precise biological function of STAG2 in this cancer is not well understood.

Purpose of the Study:

  • To elucidate the role of STAG2 in maintaining chromatin architecture and regulating gene expression in Ewing sarcoma.
  • To investigate how STAG2 loss impacts the oncogenic EWS/FLI1 program and cancer progression.

Main Methods:

  • Investigated cohesin occupancy at regulatory regions using genetic suppression of STAG2.
  • Analyzed cis-chromatin interactions and gene expression changes in STAG2 knockout cells.
  • Assessed the impact of STAG2 loss on Ewing sarcoma xenograft metastasis.

Main Results:

  • STAG2-containing cohesin localizes to enhancer and PRC2-marked regions.
  • STAG2 loss causes compensatory STAG1 increase and reprograms chromatin interactions, particularly enhancer-promoter contacts.
  • Loss of STAG2 perturbs the EWS/FLI1 oncogenic program, disrupts PRC2-mediated gene regulation, and enhances metastatic potential.

Conclusions:

  • STAG2 mutations alter chromatin architecture and transcriptional programs in Ewing sarcoma.
  • Disruption of STAG2 function promotes an aggressive cancer phenotype, including enhanced metastasis.
  • STAG2 is a critical regulator of chromatin organization and gene expression in Ewing sarcoma progression.
Keywords:
EWS/FLI1Ewing sarcomaPOU3F2PRC2STAG1STAG2cohesinfusion oncoproteinmetastasis

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