Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer

Abstract

A synthetic lethality-based strategy has been developed to identify therapeutic targets in cancer harboring tumor-suppressor gene mutations, as exemplified by the effectiveness of poly ADP-ribose polymerase (PARP) inhibitors in BRCA1/2-mutated tumors. However, many synthetic lethal interactors are less reliable due to the fact that such genes usually do not perform fundamental or indispensable functions in the cell. Here, we developed an approach to identifying the "essential lethality" arising from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. We uncovered the cohesion subunit SA1 as a putative synthetic-essential target in cancers carrying inactivating mutations of its paralog, SA2. In SA2-deficient Ewing sarcoma and bladder cancer, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival, and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells led to premature chromatid separation, dramatic extension of mitotic duration, and consequently, lethal failure of cell division. More importantly, depletion of SA1 rendered those SA2-mutated cells more susceptible to DNA damage, especially double-strand breaks (DSBs), due to reduced functionality of DNA repair. Furthermore, inhibition of SA1 sensitized the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors.

STAG2 cohesin is essential for heart morphogenesis

“…In summary, we here show that cells lacking cohesin-STAG2 are viable both in vitro (tissue culture) and in vivo (in embryos and adult tissues), confirming that cohesin-STAG1 is sufficient to fulfill essential cohesin functions ( 8, 9 ). However, their decreased proliferation and altered transcriptomes lead to embryonic lethality, a result that provides further compelling evidence for cell- and tissue-specific roles of the two cohesin complexes and how their dysfunction may contribute to disease.…”

“…Results in human cells are in line with these findings, although the extent of cohesion defects reported in the absence of STAG2 is variable. In any case, a single variant is sufficient to maintain cell viability in culture ( 6, 8, 9 ).…”

Sestrin 3 Protects Against Diet‐Induced Nonalcoholic Steatohepatitis in Mice Through Suppression of Transforming Growth Factor β Signal Transduction

“…Liver RNA samples were submitted for RNA‐seq analysis at the Center for Medical Genomics at Indiana University School of Medicine. RNA‐seq data analysis was performed as described . The RNA‐seq data were deposited at the National Center for Biotechnology Information Gene Expression Omnibus database with the accession number GSE130642.…”

“…RNA-seq data analysis was performed as described. (16) The RNA-seq data were deposited at the National Center for Biotechnology Information Gene Expression Omnibus database with the accession number GSE130642.…”

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

“…The Stag subunits differ from core cohesin subunits Rad21, Smc1 and Smc3 in that they have redundant roles in cell division, such that a complete loss of Stag2 is tolerated due to partial compensation by Stag1. In addition, Stag1 preferentially associates with CTCF to organise TADs whereas Stag2 mediates short-range cell-specific interactions (van der Lelij et al, 2017; Liu et al, 2018; Cuadrado and Losada, 2020). In mice, homozygous loss of Stag1 is lethal at embryonic day 11.5 (E11.5) (Remeseiro et al, 2012a).…”