Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA; Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA; Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC 27710, USA.
Cell Rep. 2019 Sep 3;28(10):2501-2508.e4. doi: 10.1016/j.celrep.2019.07.107.
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.
尽管最近取得了进展，但肾细胞癌 (RCC) 的不良预后表明需要新的治疗方法。铁死亡是一种受调控的细胞死亡形式，可能对 RCC 具有治疗潜力；然而，关于铁死亡易感性的决定因素，还有很多未知。我们发现铁死亡易感性受细胞密度和融合度的影响很大。由于细胞密度调节 Hippo-YAP/TAZ 通路，我们研究了 Hippo 通路效应物在铁死亡中的作用。TAZ 在 RCC 中大量表达，并经历密度依赖性的核或细胞质易位。TAZ 缺失赋予铁死亡抗性，而 TAZS89A 的过表达则使细胞对铁死亡敏感。此外，TAZ 调节上皮膜蛋白 1 (EMP1) 的表达，而 EMP1 反过来又诱导烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶 4 (NOX4) 的表达，NOX4 是一种富含肾脏的活性氧 (ROS) 生成酶，对铁死亡至关重要。这些发现表明，受细胞密度调控的铁死亡是由 TAZ 通过调节 EMP1-NOX4 介导的，这表明其在 RCC 和其他 TAZ 激活的肿瘤中的治疗潜力。
