ABSTRACT: Cervia LD, Shibue T, Borah AA, Gaeta B, He L, Leung L, Li N, Moyer S, Shim B, Dumont N, Gonzalez A, Bick N, Kazachkova M, Dempster JM, Krill-Burger JM, Piccioni F, Udeshi ND, Olive ME, Carr SA, Root DE, McFarland JM, Vazquez F, Hahn WC. 2022.
Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 726 cancer cell lines to identify selective co-essentiality modules and found a ubiquitination cascade composed of UBA6, BIRC6, KCMF1 and UBR4, which encode an E1, E2 and two heterodimeric E3 subunits, respectively, as required for the survival of a subset of epithelial tumors. Suppressing BIRC6 in cell lines dependent on this ubiquitin ligase complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) signaling by upregulation of the heme-regulated inhibitor (HRI), a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations highlight a ubiquitin ligase complex regulating ISR and identify this complex as a potential therapeutic target for a subset of epithelial cancers.
Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 726 cancer cell lines to identify selective co-essentiality modules and found a ubiquitination cascade composed of UBA6, BIRC6, KCMF1 and UBR4, which encode an E1, E2 and two heterodimeric E3 subunits, respectively, as required for the survival of a subset of epithelial tumors. Suppressing BIRC6 in cell lines dependent on this ubiquitin ligase complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) signaling by upregulation of the heme-regulated inhibitor (HRI), a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations highlight a ubiquitin ligase complex regulating ISR and identify this complex as a potential therapeutic target for a subset of epithelial cancers.
Steven A. Carr 
