期刊
EMBO MOLECULAR MEDICINE
卷 13, 期 12, 页码 -出版社
WILEY
DOI: 10.15252/emmm.202114351
关键词
ATF4; ferroptosis; Hippo signaling; liver cancer; YAP; TAZ
资金
- European Research Council (ERC) Synergy Project MERiC
- Swiss National Science Foundation Sinergia project MERiC
- Swiss Cancer League from the Theron Foundation, Vaduz (LI) [KFS-4988-02-2020-R]
- Surgery Department of the University Hospital Basel
The study reveals the critical role of YAP/TAZ in suppressing ferroptosis and establishing Sorafenib resistance in hepatocellular carcinoma (HCC). This highlights YAP/TAZ-based rewiring strategies as potential approaches to overcome HCC therapy resistance. The findings provide new insights into improving the efficacy of current therapies in cancer treatment.
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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