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

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*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

242 Citations (Scopus)

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.

Original languageEnglish
Article numbere14351
JournalEMBO Molecular Medicine
Volume13
Issue number12
DOIs
Publication statusPublished - 7 Dec 2021
Externally publishedYes

Keywords

  • ATF4
  • Hippo signaling
  • YAP/TAZ
  • ferroptosis
  • liver cancer

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