YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis

被引：382

作者：

Gao, Ruize ^{[1
]}

Kalathur, Ravi K. R. ^{[1
]}

Coto-Llerena, Mairene ^{[2
]}

Ercan, Caner ^{[2
]}

Buechel, David ^{[1
]}

Shuang, Song ^{[3
]}

Piscuoglio, Salvatore ^{[2
]}

Dill, Michael T. ^{[4
,5
]}

Camargo, Fernando D. ^{[4
,5
]}

Christofori, Gerhard ^{[1
]}

Tang, Fengyuan ^{[1
]}

机构：

[1] Univ Basel, Dept Biomed, Basel, Switzerland

[2] Univ Hosp Basel, Inst Pathol, Basel, Switzerland

[3] Friedrich Miescher Inst Biomed Res, Basel, Switzerland

[4] Boston Childrens Hosp, Stem Cell Program, Boston, MA USA

[5] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

来源：

EMBO MOLECULAR MEDICINE | 2021年 / 13卷 / 12期

基金：

瑞士国家科学基金会; 欧洲研究理事会;

关键词：

ATF4; ferroptosis; Hippo signaling; liver cancer; YAP; TAZ; HIPPO PATHWAY; CELL-DEATH; TRANSPORTER; EXPRESSION; INHIBITOR; GROWTH; GENE; TAZ;

D O I：

10.15252/emmm.202114351

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：20

共 39 条

[1] Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma [J].

Ally, Adrian ;

Balasundaram, Miruna ;

Carlsen, Rebecca ;

Chuah, Eric ;

Clarke, Amanda ;

Dhalla, Noreen ;

Holt, Robert A. ;

Jones, Steven J. M. ;

Lee, Darlene ;

Ma, Yussanne ;

Marra, Marco A. ;

Mayo, Michael ;

Moore, Richard A. ;

Mungall, Andrew J. ;

Schein, Jacqueline E. ;

Sipahimalani, Payal ;

Tam, Angela ;

Thiessen, Nina ;

Cheung, Dorothy ;

Wong, Tina ;

Brooks, Denise ;

Robertson, A. Gordon ;

Bowlby, Reanne ;

Mungall, Karen ;

Sadeghi, Sara ;

Xi, Liu ;

Covington, Kyle ;

Shinbrot, Eve ;

Wheeler, David A. ;

Gibbs, Richard A. ;

Donehower, Lawrence A. ;

Wang, Linghua ;

Bowen, Jay ;

Gastier-Foster, Julie M. ;

Gerken, Mark ;

Helsel, Carmen ;

Leraas, Kristen M. ;

Lichtenberg, Tara M. ;

Ramirez, Nilsa C. ;

Wise, Lisa ;

Zmuda, Erik ;

Gabriel, Stacey B. ;

Meyerson, Matthew ;

Cibulskis, Carrie ;

Murray, Bradley A. ;

Shih, Juliann ;

Beroukhim, Rameen ;

Cherniack, Andrew D. ;

Schumacher, Steven E. ;

Saksena, Gordon .

CELL, 2017, 169 (07) :1327-+

[2] HMGA1 Expression in Human Hepatocellular Carcinoma Correlates with Poor Prognosis and Promotes Tumor Growth and Migration in in vitro Models1 [J].

Andreozzi, Mariacarla ;

Quintavalle, Cristina ;

Benz, David ;

Quagliata, Luca ;

Matter, Matthias ;

Calabrese, Diego ;

Tosti, Nadia ;

Ruiz, Christian ;

Trapani, Francesca ;

Tornillo, Luigi ;

Fusco, Alfredo ;

Heim, Markus H. ;

Ng, Charlotte K. Y. ;

Pallante, Pierlorenzo ;

Terracciano, Luigi M. ;

Piscuoglio, Salvatore .

NEOPLASIA, 2016, 18 (12) :724-731

[3] Cutoff Finder: A Comprehensive and Straightforward Web Application Enabling Rapid Biomarker Cutoff Optimization [J].

Budczies, Jan ;

Klauschen, Frederick ;

Sinn, Bruno V. ;

Gyoerffy, Balazs ;

Schmitt, Wolfgang D. ;

Darb-Esfahani, Silvia ;

Denkert, Carsten .

PLOS ONE, 2012, 7 (12)

[4] ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner [J].

Chen, D. ;

Fan, Z. ;

Rauh, M. ;

Buchfelder, M. ;

Eyupoglu, I. Y. ;

Savaskan, N. .

ONCOGENE, 2017, 36 (40) :5593-5608

[5] High Expression of FAP in Colorectal Cancer Is Associated With Angiogenesis and Immunoregulation Processes [J].

Coto-Llerena, Mairene ;

Ercan, Caner ;

Kancherla, Venkatesh ;

Taha-Mehlitz, Stephanie ;

Eppenberger-Castori, Serenella ;

Soysal, Savas D. ;

Ng, Charlotte K. Y. ;

Bolli, Martin ;

von Flue, Markus ;

Nicolas, Guillaume P. ;

Terracciano, Luigi M. ;

Fani, Melpomeni ;

Piscuoglio, Salvatore .

FRONTIERS IN ONCOLOGY, 2020, 10

[6] Tead2 expression levels control the subcellular distribution of Yap and Taz, zyxin expression and epithelial-mesenchymal transition [J].

Diepenbruck, Maren ;

Waldmeier, Lorenz ;

Ivanek, Robert ;

Berninger, Philipp ;

Arnold, Phil ;

van Nimwegen, Erik ;

Christofori, Gerhard .

JOURNAL OF CELL SCIENCE, 2014, 127 (07) :1523-1536

[7] Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis [J].

Dixon, Scott J. ;

Patel, Darpan ;

Welsch, Matthew ;

Skouta, Rachid ;

Lee, Eric ;

Hayano, Miki ;

Thomas, Ajit G. ;

Gleason, Caroline ;

Tatonetti, Nicholas ;

Slusher, Barbara S. ;

Stockwell, Brent R. .

ELIFE, 2014, 3

[8] Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death [J].

Dixon, Scott J. ;

Lemberg, Kathryn M. ;

Lamprecht, Michael R. ;

Skouta, Rachid ;

Zaitsev, Eleina M. ;

Gleason, Caroline E. ;

Patel, Darpan N. ;

Bauer, Andras J. ;

Cantley, Alexandra M. ;

Yang, Wan Seok ;

Morrison, Barclay, III ;

Stockwell, Brent R. .

CELL, 2012, 149 (05) :1060-1072

[9] STAR: ultrafast universal RNA-seq aligner [J].

Dobin, Alexander ;

Davis, Carrie A. ;

Schlesinger, Felix ;

Drenkow, Jorg ;

Zaleski, Chris ;

Jha, Sonali ;

Batut, Philippe ;

Chaisson, Mark ;

Gingeras, Thomas R. .

BIOINFORMATICS, 2013, 29 (01) :15-21

[10] Using GOstats to test gene lists for GO term association [J].

Falcon, S. ;

Gentleman, R. .

BIOINFORMATICS, 2007, 23 (02) :257-258

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