CRISPR screens uncover protective effect of PSTK as a regulator of chemotherapy-induced ferroptosis in hepatocellular carcinoma

Molecular Cancer

Jing Zhao¹  Li Li²  Xiaosong Rao³  Gaoda Ju⁴  Yiran Chen⁴  Tao Xing⁴  Jun Liang⁵  Jizhong Lou⁶  Yang Cui⁶  Jie Lan⁶  Guangtao Song⁷ 

[1] Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, 266000, Qingdao, China;Department of Oncology, Peking University International Hospital, 102206, Beijing, China;Department of Pathology, Boao Evergrande International Hospital, 571400, Qionghai, Hainan, China;Department of Pathology, Peking University International Hospital, 102206, Beijing, China;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Oncology, Peking University Cancer Hospital and Institute, 1 Life Park Road, Life Science Park of Zhongguancun, Changping, 102206, Beijing, P.R. China;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Oncology, Peking University Cancer Hospital and Institute, 1 Life Park Road, Life Science Park of Zhongguancun, Changping, 102206, Beijing, P.R. China;Department of Oncology, Peking University International Hospital, 102206, Beijing, China;Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China;Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China;Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), 510005, Guangzhou, China;

关键词: Hepatocellular carcinoma;    CRISPR library screening;    PSTK;    Ferroptosis;   

DOI  :  10.1186/s12943-021-01466-9

来源: Springer

【 摘 要 】

BackgroundHepatocellular 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.MethodsCRISPR-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.ResultsThe 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.ConclusionsThese 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.

【 授权许可】

CC BY