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 - 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 - Hippo signaling
KW - YAP/TAZ
KW - ferroptosis
KW - liver cancer
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 -