CRISPR screens uncover protective effect of PSTK as a regulator of chemotherapy-induced ferroptosis in hepatocellular carcinoma.
CRISPR screens uncover protective effect of PSTK as a regulator of chemotherapy-induced ferroptosis in hepatocellular carcinoma.
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DOI：
10.1186/s12943-021-01466-9
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发表时间：
2022-01-04
期刊：
影响因子：
37.3
通讯作者：
Liang J
中科院分区：
文献类型：
--
作者：
Chen Y;Li L;Lan J;Cui Y;Rao X;Zhao J;Xing T;Ju G;Song G;Lou J;Liang J
肝细胞癌（HCC）是最常见的癌症形式之一，与患者预后不良相关。迄今为止，治疗耐药性的出现阻碍了用于治疗HCC患者的靶向治疗的疗效。在这项研究中，我们进行了一系列CRISPR/Cas9筛选，以鉴定与能够改善HCC患者临床反应的合成致死性相关的基因。基于CRISPR的功能丧失基因筛选用于靶向HCC细胞中的18，053个蛋白质编码基因，以鉴定这些细胞中与化疗相关的合成致死基因。通过体外和体内分析来分析协同效应，同时通过RNA-seq和代谢组学分析来探索相关机制。通过高通量虚拟筛选，选择了已鉴定遗传靶点的潜在抑制剂。发现磷酸丝氨酰-tRNA激酶（PSTK）的抑制增加HCC细胞对化疗治疗的敏感性。PSTK与化疗诱导的肝癌细胞铁凋亡的抑制有关，PSTK的耗竭导致谷胱甘肽过氧化产物4（GPX 4）的失活和谷胱甘肽（GSH）代谢的破坏，这是由于硒代半胱氨酸和半胱氨酸的合成受到抑制，从而增强了靶向化疗诱导的铁凋亡。Punicalin是一种用于治疗B肝炎病毒（HBV）的药物，被鉴定为可能的PSTK抑制剂，当与索拉非尼一起应用于体外和体内治疗HCC时，其表现出协同功效。这些结果突出了PSTK作为HCC细胞中靶向治疗治疗抗性的介体的关键作用，其通过抑制铁凋亡诱导发挥作用。因此，PSTK抑制剂可能是克服HCC耐药性的理想候选药物。在线版本包含补充材料，可通过10.1186/s12943-021-01466-9获得。
Hepatocellular carcinoma (HCC) is among the most common forms of cancer and is associated with poor patient outcomes. The emergence of therapeutic resistance has hampered the efficacy of targeted treatments employed to treat HCC patients to date. In this study, we conducted a series of CRISPR/Cas9 screens to identify genes associated with synthetic lethality capable of improving HCC patient clinical responses. CRISPR-based loss-of-function genetic screens were used to target 18,053 protein-coding genes in HCC cells to identify chemotherapy-related synthetic lethal genes in these cells. Synergistic effects were analyzed through in vitro and in vivo analyses, while related mechanisms were explored through RNA-seq and metabolomics analyses. Potential inhibitors of identified genetic targets were selected through high-throughput virtual screening. The inhibition of phosphoseryl-tRNA kinase (PSTK) was found to increase HCC cell sensitivity to chemotherapeutic treatment. PSTK was associated with the suppression of chemotherapy-induced ferroptosis in HCC cells, and the depletion of PSTK resulted in the inactivation of glutathione peroxidative 4 (GPX4) and the disruption of glutathione (GSH) metabolism owing to the inhibition of selenocysteine and cysteine synthesis, thus enhancing the induction of ferroptosis upon targeted chemotherapeutic treatment. Punicalin, an agent used to treat hepatitis B virus (HBV), was identified as a possible PSTK inhibitor that exhibited synergistic efficacy when applied together with Sorafenib to treat HCC in vitro and in vivo. These results highlight a key role for PSTK as a mediator of resistance to targeted therapeutic treatment in HCC cells that functions by suppressing ferroptotic induction. PSTK inhibitors may thus represent ideal candidates for overcoming drug resistance in HCC. The online version contains supplementary material available at 10.1186/s12943-021-01466-9.
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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
影响因子：
7.6
作者：
Liu C;Cai D;Zhang L;Tang W;Yan R;Guo H;Chen X
通讯作者：
Chen X
DOI：
10.1126/science.aaw9872
发表时间：
2020-04-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badgley MA;Kremer DM;Maurer HC;DelGiorno KE;Lee HJ;Purohit V;Sagalovskiy IR;Ma A;Kapilian J;Firl CEM;Decker AR;Sastra SA;Palermo CF;Andrade LR;Sajjakulnukit P;Zhang L;Tolstyka ZP;Hirschhorn T;Lamb C;Liu T;Gu W;Seeley ES;Stone E;Georgiou G;Manor U;Iuga A;Wahl GM;Stockwell BR;Lyssiotis CA;Olive KP
通讯作者：
Olive KP
影响因子：
56.9
作者：
Kryukov, GV;Castellano, S;Gladyshev, VN
通讯作者：
Gladyshev, VN
影响因子：
17.1
作者：
Guo, Xuliang;Liu, Fang;Zhao, Yanjun
通讯作者：
Zhao, Yanjun