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The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma

39 Pages Posted: 26 Feb 2019 Sneak Peek Status: Review Complete

See all articles by Wen-Hsua Yang

Wen-Hsua Yang

Duke University - Department of Molecular Genetics and Microbiology; Duke University - Center for Genomic and Computational Biology; Duke University - Department of Biochemistry

Chien-Kuang Cornelia Ding

Duke University - Department of Molecular Genetics and Microbiology; Duke University - Center for Genomic and Computational Biology

Tianai Alice Sun

Duke University - Department of Molecular Genetics and Microbiology; Duke University - Center for Genomic and Computational Biology

David Shiaowen Hsu

Duke University - Department of Medicine

Jen-Tsan Ashley Chi

Duke University - Department of Molecular Genetics and Microbiology; Duke University - Center for Genomic and Computational Biology

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Abstract

Despite recent advances, the poor outcomes of renal cell carcinoma (RCC) still necessitate novel therapeutics. RCC is highly susceptible to ferroptosis, a novel form of regulated cell death with disease relevance. While ferroptosis may have therapeutic potential, much remains unknown about the determinants of ferroptosis susceptibility. We found that the ferroptosis susceptibility is highly influenced by cell confluency. RCC grown at low density is highly susceptible to ferroptosis, but exhibits resistance at high density. Because cell density regulates Hippo-YAP/TAZ pathway, we investigated the roles of Hippo pathway effectors in the ferroptosis. TAZ is abundantly expressed in RCC and undergoes density-dependent nuclear/cytosolic translocation. TAZ removal confers ferroptosis resistance, while overexpression TAZS89A sensitizes cells to ferroptosis. Furthermore, TAZ regulates the expression of EMP1 that, in turn, induces the expression of NOX4, a renal-enriched ROS-generating enzyme essential for ferroptosis. Collectively, the 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.

Keywords: Ferroptosis; Renal Cell Carcinoma; Erastin; Hippo pathway; WW Domain Containing Transcription Regulator 1 (TAZ); Epithelial Membrane Protein 1 (EMP1); NADPH Oxidase 4 (NOX4)

Suggested Citation

Yang, Wen-Hsua and Cornelia Ding, Chien-Kuang and Sun, Tianai Alice and Hsu, David Shiaowen and Chi, Jen-Tsan Ashley, The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma (January 16, 2019). Available at SSRN: https://ssrn.com/abstract=3316797 or http://dx.doi.org/10.2139/ssrn.3316797
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Wen-Hsua Yang

Duke University - Department of Molecular Genetics and Microbiology

Durham, NC 27710
United States

Duke University - Center for Genomic and Computational Biology

Durham, NC 27710
United States

Duke University - Department of Biochemistry

Durham, NC 27710
United States

Chien-Kuang Cornelia Ding

Duke University - Department of Molecular Genetics and Microbiology

Durham, NC 27710
United States

Duke University - Center for Genomic and Computational Biology

Durham, NC 27710
United States

Tianai Alice Sun

Duke University - Department of Molecular Genetics and Microbiology

Durham, NC 27710
United States

Duke University - Center for Genomic and Computational Biology

Durham, NC 27710
United States

David Shiaowen Hsu

Duke University - Department of Medicine

Durham, NC 27710
United States

Jen-Tsan Ashley Chi (Contact Author)

Duke University - Department of Molecular Genetics and Microbiology ( email )

Durham, NC 27710
United States

Duke University - Center for Genomic and Computational Biology ( email )

Durham, NC 27710
United States

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