YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis.
YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis.
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YAP/TAZ和ATF4通过预防铁下垂驱动肝癌对索拉非尼的耐药。
DOI：
10.15252/emmm.202114351
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发表时间：
2021-12-07
影响因子：
11.1
通讯作者：
Tang F
中科院分区：
文献类型：
--
作者：
Gao R;Kalathur RKR;Coto-Llerena M;Ercan C;Buechel D;Shuang S;Piscuoglio S;Dill MT;Camargo FD;Christofori G;Tang F
了解癌症中逃避性耐药的机制是提高当前治疗效果的未满足的医学需求。在这项研究中，shRNA介导的合成致死筛选和转录组学分析的结合显示，转录因子YAP/TAZ通过抑制索拉非尼诱导的铁凋亡，是肝细胞癌（HCC）中索拉非尼耐药的关键驱动因素。在机制上，YAP/TAZ以一种依赖于TEAD的方式诱导SLC7A11的表达，SLC7A11是维持细胞内谷胱甘肽稳态的关键转运体，从而使HCC细胞克服索拉非尼诱导的铁凋亡。同时，YAP/TAZ维持ATF4的蛋白稳定性、核定位和转录活性，进而协同诱导SLC7A11的表达。我们的研究揭示了YAP/TAZ在抑制铁上吊中的关键作用，从而在HCC中建立索拉非尼耐药，强调了基于YAP/TAZ的重新布线策略是克服HCC治疗耐药的潜在方法。大多数接受索拉非尼治疗的肝癌患者出现耐药性，患者死于疾病。合成致死筛选确定了一个调控回路，该回路可防止铁凋亡并促进癌细胞存活，从而促进对索拉非尼的耐药性。
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. Resistance to therapy occurs in most liver cancer patients treated with Sorafenib, and patients succumb to the disease. A synthetic lethal screen identified a regulatory circuit, which prevents ferroptosis and promotes cancer cell survival, thus promoting resistance to Sorafenib.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1126/science.1199010
发表时间：
2011-04-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Heallen T;Zhang M;Wang J;Bonilla-Claudio M;Klysik E;Johnson RL;Martin JF
通讯作者：
Martin JF
p62-Keap1-NRF2 通路的激活可防止肝细胞癌细胞中的铁死亡。
DOI：
10.1002/hep.28251
发表时间：
2016-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Sun X;Ou Z;Chen R;Niu X;Chen D;Kang R;Tang D
通讯作者：
Tang D
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network