title: Synthetic lethal targeting of superoxide dismutase 1 selectively kills RAD54B-deficient colorectal cancer cells.
abstract: Synthetic lethality is a rational approach to identify candidate drug targets for selective killing of cancer cells harboring somatic mutations that cause chromosome instability (CIN). To identify a set of the most highly connected synthetic lethal partner genes in yeast for subsequent testing in mammalian cells, we used the entire set of 692 yeast CIN genes to query the genome-wide synthetic lethal datasets. Hierarchical clustering revealed a highly connected set of synthetic lethal partners of yeast genes whose human orthologs are somatically mutated in colorectal cancer. Testing of a small matrix of synthetic lethal gene pairs in mammalian cells suggested that members of a pathway that remove reactive oxygen species that cause DNA damage would be excellent candidates for further testing. We show that the synthetic lethal interaction between budding yeast rad54 and sod1 is conserved within a human colorectal cancer context. Specifically, we demonstrate RAD54B-deficient cells are selectively killed relative to controls via siRNA-based silencing and chemical inhibition and further demonstrate that this interaction is conserved in an unrelated cell type. We further show that the DNA double strand breaks, resulting from increased reactive oxygen species following SOD1 inhibition, persist within the RAD54B-deficient cells and result in apoptosis. Collectively, these data identify SOD1 as a novel candidate cancer drug target and suggest that SOD1 inhibition may have broad-spectrum applicability in a variety of tumor types exhibiting RAD54B deficiencies.
authors.affiliation: Manitoba Institute of Cell Biology and Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, R3E 0V9, Canada.
authors.forename: Babu V
authors.initials: BV
authors.lastname: Sajesh
authors.forename: Melanie
authors.initials: M
authors.lastname: Bailey
authors.forename: Zelda
authors.initials: Z
authors.lastname: Lichtensztejn
authors.forename: Philip
authors.initials: P
authors.lastname: Hieter
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: McManus
mesh_terms: D000077584:2-Methoxyestradiol; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000628:therapy; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004265:DNA Helicases / Q000172:deficiency* / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005800:Genes, Fungal; D005804:Genes, Lethal; D045325:HCT116 Cells; D006801:Humans; D008982:Molybdenum / Q000494:pharmacology; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: D009687:Nuclear Proteins; C491221:RAD54B protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D004958:Estradiol; D000077584:2-Methoxyestradiol; D008982:Molybdenum; C020809:tetrathiomolybdate; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D004265:DNA Helicases
keywords: RAD54B; colorectal cancer; reactive oxygen species; superoxide dismutase 1; synthetic lethality