Abstract
Recent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.
Highlights
Cohesin is a highly conserved ring-shaped protein complex that is thought to topologically embrace chromatid fibers (Peters and Nishiyama, 2012), which is essential for sister chromatid cohesion and chromosome segregation in eukaryotes
We hypothesized that STAG2 loss could alter the properties and function of the cohesin complex leading to unique vulnerabilities of STAG2 mutated cells
Expression of an short-interfering RNA (siRNA)-resistant STAG1 transgene alleviated the anti-proliferative effect of STAG1 but not of SGOL1 siRNA duplexes in STAG2- HCT 116 cells demonstrating the specificity of the siRNA treatment (Figure 1—figure supplement 2)
Summary
Cohesin is a highly conserved ring-shaped protein complex that is thought to topologically embrace chromatid fibers (Peters and Nishiyama, 2012), which is essential for sister chromatid cohesion and chromosome segregation in eukaryotes. The cohesin subunits SMC1, SMC3 and RAD21 ( called SCC1) comprise the core ring of the complex. A fourth universally conserved subunit, a HEAT repeat protein of the Scc3/STAG family, peripherally associates with the core cohesin ring by binding to RAD21 (Toth et al, 1999), and is required for the dynamic association of cohesin with chromatin (Hu et al, 2011; Murayama and Uhlmann, 2014). Human somatic cells express two paralogs of this protein, called STAG1 and STAG2 (Losada et al, 2000; Sumara et al, 2000)
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