EMBO Molecular Medicine (Dec 2021)

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

DOI
https://doi.org/10.15252/emmm.202114351
Journal volume & issue
Vol. 13, no. 12
pp. n/a – n/a

Abstract

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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.

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