Results Identification of YAP/TAZ as key drivers of Sorafenib resistance Our study highlights YAP/TAZ as novel repressors of ferroptosis and, thus, as attractive therapeutic targets to overcome therapy resistance. Moreover, the data suggest YAP/TAZ as key chaperones in stabilizing ATF4 protein and sustaining its nuclear transcriptional activity. In a TEAD- and ATF4-dependent manner, YAP/TAZ induce the expression of SLC7A11, thus assisting cells in overcoming Sorafenib-induced ferroptosis.
Here, we aimed at dissecting the molecular drivers of Sorafenib resistance in HCC and identified YAP/TAZ as negative regulators of ferroptosis.
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Previous studies have suggested the Hippo-YAP/TAZ pathway is a key driver of ferroptosis in epithelial tumors (Wu et al, 2019 Yang et al, 2019). YAP/TAZ are well-characterized transcriptional effectors of Hippo signaling involved in a variety of physio-pathological processes, including tumorigenesis and tissue regeneration (Pan, 2010 Harvey et al, 2013). Small pharmacological inhibitors, including the GPX4 inhibitor RS元, and Erastin and Sorafenib as direct inhibitors of xCT-mediated import function, are widely used for the induction of ferroptosis (Dixon et al, 2012 Lachaier et al, 2014). Hence, ferroptosis can be potently induced by cysteine deprivation and GPX4 inhibition. GSH, among many functions, is also used as a substrate of phospholipid-hydroxyperoxide-glutathione-peroxidase (GPX4) to catalyze the detoxification of phospholipid hydroperoxides (Lachaier et al, 2014). Among the core regulatory components, the cystine-glutamate antiporter known as system Xc- or xCT (SLC7A11, encoded by the gene SLC7A11) imports cystine for the de novo synthesis of the important antioxidant peptide glutathione (GSH). Thus, delineating the mechanisms underlying evasive resistance of HCC is an unmet medical need and may add to a general understanding of therapy resistance in other cancer types as well.įerroptosis is an emerging type of cell death induced by metal iron and reactive oxygen species (ROS) and driven by lipid peroxidation (Dixon et al, 2012 Jiang et al, 2021). Although cancer therapies have substantially improved clinical outcome (Kudo et al, 2018 Lee et al, 2020), patients invariably experience cancer relapse. Hepatocellular carcinoma (HCC) represents about 90% of all cases of primary liver cancer (Llovet et al, 2008, 2016). Liver cancer is the second leading cause of cancer-related mortality in patients. These results suggest the possibility to re-sensitize therapy-resistant liver cancers to Sorafenib treatment by pharmacologically repressing the antioxidant pathways regulated by YAP/TAZ and ATF4. Proof-of-concept experiments with cultured liver cancer cells and in liver cancer mouse models revealed that inhibition of these pathways prevents the development of resistance to Sorafenib therapy. These pathways are also upregulated in tumors of Sorafenib-resistant liver cancer patients. We found that the transcriptional regulators YAP/TAZ and ATF4 cooperatively induce the expression of genes required for antioxidant pathways, which are critical to prevent cancer cell death by ferroptosis. We investigated the molecular mechanism underlying the development and maintenance of resistance to Sorafenib therapy in liver cancer cells.
While treatment of liver cancer patients with Sorafenib, the current treatment of choice for advanced hepatocellular carcinoma, induces in most cases initial beneficial effects, resistance to Sorafenib therapy eventually occurs, tumors relapse, and patients succumb to the disease. 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. 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. 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. 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. Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies.
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