A Ubiquitination Cascade Regulating the Integrated Stress Response and Survival in Carcinomas

Systematic identifi cation of signaling pathways required for the fitness of can-cer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 1,086 cancer cell lines to identify selective coessentiality modules and found that a ubiquitin ligase complex composed of UBA6 , BIRC6 , KCMF1, and UBR4 is required for the survival of a subset of epithelial tumors that exhibit a high degree of aneuploidy. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo . Mechanistically, BIRC6 suppression resulted in selective activa-tion of the integrated stress response (ISR) by stabilization of the heme-regulated inhibitor, a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new thera-peutic strategy.SIGNIFICANCE: We describe the identifi cation of a heretofore unrecognized ubiquitin ligase complex that prevents the aberrant activation of the ISR in a subset of cancer cells. This provides a novel insight on the regulation of ISR and exposes a therapeutic opportunity to selectively eliminate these cancer cells.

Automated summary

By measuring gene essentiality in 1,086 cancer cell lines, we identified a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1, and UBR4 that is crucial for the survival of a subset of epithelial tumors with high aneuploidy. Inhibiting BIRC6 in cell lines dependent on this complex significantly reduced cell fitness in vitro and resulted in tumor regression in vivo. Mechanistically, BIRC6 suppression activated the integrated stress response (ISR) by stabilizing the heme-regulated inhibitor, which is a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. This discovery provides insights into the regulation of ISR and offers a potential therapeutic strategy.