TY - JOUR
T1 - YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis
AU - Gao, Ruize
AU - Kalathur, Ravi K.R.
AU - Coto-Llerena, Mairene
AU - Ercan, Caner
AU - Buechel, David
AU - Shuang, Song
AU - Piscuoglio, Salvatore
AU - Dill, Michael T.
AU - Camargo, Fernando D.
AU - Christofori, Gerhard
AU - Tang, Fengyuan
N1 - Funding Information:
We thank A. Kapus, B. Gan, and A. Hergovich for providing plasmid constructs. We thank C. Beisel and the Genomics Facility Basel for RNA and barcode sequencing. We are grateful to E. Panoussis, U. Schmieder, and the DBM animal core facility for the support with animal experiments, P. Lorentz and the DBM microscopy facility for imaging, and M.N. Hall and J. Tchorz for critical suggestions. We thank the tissue biobank of the Institute of Pathology at the University Hospital of Basel for providing multi-tissue array slides. This work was supported by the European Research Council (ERC) Synergy Project MERiC and the Swiss National Science Foundation Sinergia project MERiC. S.P. was supported by the Swiss Cancer League (KFS-4988-02-2020-R) from the Theron Foundation, Vaduz (LI) and from the Surgery Department of the University Hospital Basel.
Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2021/12/7
Y1 - 2021/12/7
N2 - 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.
AB - 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.
KW - ATF4
KW - ferroptosis
KW - Hippo signaling
KW - liver cancer
KW - YAP/TAZ
UR - http://www.scopus.com/inward/record.url?scp=85117168507&partnerID=8YFLogxK
U2 - 10.15252/emmm.202114351
DO - 10.15252/emmm.202114351
M3 - Article
C2 - 34664408
AN - SCOPUS:85117168507
SN - 1757-4676
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 12
M1 - e14351
ER -