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Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts

Petra van der Lelij1, Simone Lieb2, Julian Jude1

  • 1Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.

Elife
|July 11, 2017
PubMed

Insights

Mutations in the STAG2 gene create a vulnerability that can be targeted by inhibiting STAG1. This synthetic lethal interaction causes cell death in cancer cells with STAG2 mutations, offering a potential new cancer therapy.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Biology

Background:

  • Recurrent mutations in the cohesin complex are prevalent in human cancers.
  • STAG2 is the most frequently mutated subunit within the cohesin complex.

Purpose of the Study:

  • To investigate the functional consequences of STAG2 mutations.
  • To identify therapeutic vulnerabilities associated with STAG2 mutations.

Main Methods:

  • Analysis of synthetic lethal interactions between STAG1 and STAG2.
  • Cell proliferation assays in cancer cell lines with varying STAG2 expression.
  • Sister chromatid cohesion assays.

Main Results:

  • STAG2 mutations lead to a synthetic lethal interaction with STAG1.
  • Loss of STAG1 causes mitotic catastrophe and apoptosis specifically in STAG2-mutated cells.
  • STAG1 inactivation inhibits proliferation in STAG2-mutated bladder cancer and Ewing sarcoma cells.
  • Restoring STAG2 expression reduces the dependency on STAG1.

Conclusions:

  • STAG1 and STAG2 redundantly maintain sister chromatid cohesion and cell survival.
  • STAG1 is a critical vulnerability in cancers with STAG2 mutations.
  • Targeting STAG1 via synthetic lethality offers a promising therapeutic strategy for cohesin-mutated cancers.
Keywords:
cancer biologycell biologycell divisionchromosomescohesingenetic interactionhumanmitosissynthetic lethality

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