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Abstract 4472: The hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma

Ferroptosis is a newly appreciated lipid peroxidation-dependent regulated cell death with relevance for many human diseases, which may be a tumor suppression mechanism and may have antitumor potential. Elucidation of the mechanism is therefore important. Here, we reported that ferroptosis sensitivity is significantly influenced by cell density. The effectors of the Hippo pathway, YAP/TAZ, are the molecular sensors of cell density that regulate cell proliferation, survival, and organ size determination. Therefore, we determined the potential role of YAP/TAZ in regulating ferroptosis sensitivities. RCC cell lines and RCC PDX tumor cells mainly express TAZ that undergoes density-dependent nuclear translocation. Importantly, the removal of TAZ confers ferroptosis resistance, while the expression of constructively active TAZ sensitizes cells to ferroptosis. Mechanistically, we found that TAZ knockdown reduced ferroptosis through the repression of its target gene, EMP1. EMP1 affects ferroptosis through the regulation of NOX4 and lipid peroxidation. Collectively, we have shown that the ferroptosis can be regulated by non-genetic factors, such as cell density, through the Hippo pathway and suggest the therapeutic potential of ferroptosis-inducing agent, such as erastin, for TAZ-activated tumors. Citation Format: Wen-Hsuan Yang, Jen-Tsan Chi. The hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4472.