The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma

Abstract

Summary: Despite recent advances, the poor outcomes in renal cell carcinoma (RCC) suggest novel therapeutics are needed. Ferroptosis is a form of regulated cell death, which may have therapeutic potential toward RCC; however, much remains unknown about the determinants of ferroptosis susceptibility. We found that ferroptosis susceptibility is highly influenced by cell density and confluency. Because cell density regulates the Hippo-YAP/TAZ pathway, we investigated the roles of the Hippo pathway effectors in ferroptosis. TAZ is abundantly expressed in RCC and undergoes density-dependent nuclear or cytosolic translocation. TAZ removal confers ferroptosis resistance, whereas overexpression of TAZS89A sensitizes cells to ferroptosis. Furthermore, TAZ regulates the expression of Epithelial Membrane Protein 1 (EMP1), which, in turn, induces the expression of nicotinamide adenine dinucleotide phosphate (NADPH) Oxidase 4 (NOX4), a renal-enriched reactive oxygen species (ROS)-generating enzyme essential for ferroptosis. These findings reveal that cell density-regulated ferroptosis is mediated by TAZ through the regulation of EMP1-NOX4, suggesting its therapeutic potential for RCC and other TAZ-activated tumors. : Yang et al. show that ferroptosis sensitivity in renal cell carcinoma (RCC) is regulated by cell density through the TAZ-EMP1-NOX4 pathway. These findings reveal TAZ as a genetic determinant of ferroptosis in RCC. In addition, ferroptosis may hold therapeutic potential for RCC and other TAZ-activated tumors. Keywords: cell density, ferroptosis, renal cell carcinoma, erastin, Hippo pathway, WW Domain Containing Transcription Regulator 1, TAZ, Epithelial Membrane Protein 1, EMP1, NADPH Oxidase 4, NOX4