Abstract 1950: A ubiquitination cascade regulates the integrated stress response and epithelial cancer survival

Abstract Systematic identification of signaling pathways required for the viability of cancer cells will facilitate the development of novel cancer therapies. We used gene essentiality measurements in 726 cancer cell lines to identify selective co-essentiality modules and found a functional ubiquitination cascade containing UBA6, BIRC6, KCMF1 and UBR4, which encode an E1, E2, and two heterodimeric E3 subunits, respectively, as a vulnerability in a subset of epithelial tumors. Suppressing BIRC6 in cancer cell lines that are dependent on this ubiquitination cascade led to a strong reduction in cell fitness in vitro, and to potent tumor regression and metastasis suppression in vivo. Mechanistically, BIRC6 suppression resulted in selective and robust activation of the integrated stress response (ISR) signaling via upregulation of the heme-regulated inhibitor (HRI). Using proteomic profiling, we found that HRI itself is a key degradation target of the UBA6/BIRC6/KCMF1/UBR4 cascade. These observations demonstrate a protein ubiquitination cascade regulating ISR and highlight the potential of this cascade as a novel therapeutic target for a subset of epithelial cancers. Citation Format: Lisa D. Cervia, Tsukasa Shibue, Benjamin Gaeta, Ashir Borah, Lisa Leung, Naomi Li, Nancy Dumont, Alfredo Gonzalez, Nolan Bick, Mariya Kazachkova, Joshua Dempster, John M. Krill-Burger, Namrata Udeshi, Meagan Olive, Steven A. Carr, David E. Root, Federica Piccioni, James M. McFarland, Francisca Vazquez, William C. Hahn. A ubiquitination cascade regulates the integrated stress response and epithelial cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1950.