Cohesin mutations are synthetic lethal with stimulation of WNT signaling

Abstract

Mutations in genes encoding subunits of the cohesin complex are common in several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations of genes encoding cohesin subunits SMC3, RAD21 and STAG2 and screened for synthetic lethality with 3,009 FDA-approved compounds. The screen identified several compounds that interfere with transcription, DNA damage repair and the cell cycle. Unexpectedly, one of the top ‘hits’ was a GSK3 inhibitor, an agonist of Wnt signaling. We show that sensitivity to GSK3 inhibition is likely due to stabilization of β-catenin in cohesin mutant cells, and that Wnt-responsive gene expression is highly sensitized in STAG2-mutant CMK leukemia cells. Moreover, Wnt activity is enhanced in zebrafish mutant for cohesin subunit rad21. Our results suggest that cohesin mutations could progress oncogenesis by enhancing Wnt signaling, and that targeting the Wnt pathway may represent a novel therapeutic strategy for cohesin mutant cancers.

Cohesin Components Stag1 and Stag2 Differentially Influence Haematopoietic Mesoderm Development in Zebrafish Embryos

“…Bmp signaling cooperates with Wnt signaling to promote blood fate through activation of homeobox transcription factors Cdx1 and Cdx4 (Lengerke et al, 2008 ). Previous studies show that mutations in cohesin subunits interfere with canonical Wnt signaling (Avagliano et al, 2017 ; Chin et al, 2020 ), so it is possible that loss of Stag1a or Stag2b differentially affect the balance of Bmp and Wnt signaling that directs the production of scl -positive cells. Further experimentation will be needed to determine whether this is the case.…”

Discovery of Latent Drivers from Double Mutations in Pan-Cancer Data Reveal their Clinical Impact

“…Another interesting case is the double mutations in the cohesin complex. Mutated cohesin can enhance Wnt signaling by stabilizing beta-catenin [44]. Targeting Wnt signaling in cohesin mutant cancer cells was proposed as a novel therapeutic strategy.…”

Cohesin components Stag1 and Stag2 differentially influence haematopoietic mesoderm development in zebrafish embryos

“…Bmp signalling cooperates with Wnt signalling to promote blood fate through activation of homeobox transcription factors Cdx1 and Cdx4 (Lengerke et al, 2008). Previous studies show that mutations in cohesin subunits interfere with canonical Wnt signalling (Avagliano et al, 2017; Chin et al, 2020), so it is possible that loss of Stag1a or Stag2b differentially affect the balance of Bmp and Wnt signalling that directs the production of scl -positive cells. Further experimentation will be needed to determine whether this is the case.…”