Year: 2019
Type: article
Abstract: 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.
Source: Cell Reports
Institutions: Duke University, Duke Medical Center
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: TRIGGERING HUMAN ANTITUMOR STRINGENT RESPONSE TO TARGET RECURRENT OVARIAN CANCER, G2040153736, G2800195642, Development of MESH1 inhibitors to treat ferroptosis-associated neurodegeneration, HUMAN STRINGENT RESPONSE AS NOVEL THERAPEUTIC APPROACHES FOR BREAST CANCERS, G4095814686, G4119534169, G5850682332, Biochemical and functional investigation of the novel enzymatic activities of MESH1, Cancer Center Support Grant (CCSG)
OpenAlex ID: W2972164676