YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis
Abstract Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA‐mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-12-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202114351 |
| _version_ | 1797287477692596224 |
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| author | Ruize Gao Ravi K R Kalathur Mairene Coto‐Llerena Caner Ercan David Buechel Song Shuang Salvatore Piscuoglio Michael T Dill Fernando D Camargo Gerhard Christofori Fengyuan Tang |
| author_facet | Ruize Gao Ravi K R Kalathur Mairene Coto‐Llerena Caner Ercan David Buechel Song Shuang Salvatore Piscuoglio Michael T Dill Fernando D Camargo Gerhard Christofori Fengyuan Tang |
| author_sort | Ruize Gao |
| collection | DOAJ |
| description | Abstract Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA‐mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib‐induced ferroptosis. Mechanistically, in a TEAD‐dependent manner, YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib‐induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization, and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovers a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ‐based rewiring strategies as potential approaches to overcome HCC therapy resistance. |
| first_indexed | 2024-03-07T18:33:41Z |
| format | Article |
| id | doaj.art-0a45c210533448afa645988d3bfff73d |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:33:41Z |
| publishDate | 2021-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-0a45c210533448afa645988d3bfff73d2024-03-02T05:14:07ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-12-011312n/an/a10.15252/emmm.202114351YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosisRuize Gao0Ravi K R Kalathur1Mairene Coto‐Llerena2Caner Ercan3David Buechel4Song Shuang5Salvatore Piscuoglio6Michael T Dill7Fernando D Camargo8Gerhard Christofori9Fengyuan Tang10Department of Biomedicine University of Basel Basel SwitzerlandDepartment of Biomedicine University of Basel Basel SwitzerlandInstitute of Pathology University Hospital Basel Basel SwitzerlandInstitute of Pathology University Hospital Basel Basel SwitzerlandDepartment of Biomedicine University of Basel Basel SwitzerlandFriedrich Miescher Institute for Biomedical Research Basel SwitzerlandInstitute of Pathology University Hospital Basel Basel SwitzerlandStem Cell Program Boston Children's Hospital Boston MA USAStem Cell Program Boston Children's Hospital Boston MA USADepartment of Biomedicine University of Basel Basel SwitzerlandDepartment of Biomedicine University of Basel Basel SwitzerlandAbstract Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA‐mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib‐induced ferroptosis. Mechanistically, in a TEAD‐dependent manner, YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib‐induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization, and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovers a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ‐based rewiring strategies as potential approaches to overcome HCC therapy resistance.https://doi.org/10.15252/emmm.202114351ATF4ferroptosisHippo signalingliver cancerYAP/TAZ |
| spellingShingle | Ruize Gao Ravi K R Kalathur Mairene Coto‐Llerena Caner Ercan David Buechel Song Shuang Salvatore Piscuoglio Michael T Dill Fernando D Camargo Gerhard Christofori Fengyuan Tang YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis EMBO Molecular Medicine ATF4 ferroptosis Hippo signaling liver cancer YAP/TAZ |
| title | YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis |
| title_full | YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis |
| title_fullStr | YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis |
| title_full_unstemmed | YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis |
| title_short | YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis |
| title_sort | yap taz and atf4 drive resistance to sorafenib in hepatocellular carcinoma by preventing ferroptosis |
| topic | ATF4 ferroptosis Hippo signaling liver cancer YAP/TAZ |
| url | https://doi.org/10.15252/emmm.202114351 |
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