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In vitro CRISPR screening uncovers CRTC3 as a regulator of IFN-γ-induced ferroptosis of hepatocellular carcinoma.
Li, Li; Xing, Tao; Chen, Yiran; Xu, Weiran; Fan, Bo; Ju, Gaoda; Zhao, Jing; Lin, Li; Yan, Cihui; Liang, Jun; Ren, Xiubao.
Afiliación
  • Li L; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
  • Xing T; Tianjin's Clinical Research Center for Cancer, Tianjin, China.
  • Chen Y; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
  • Xu W; Department of Oncology, Peking University International Hospital, Beijing, China.
  • Fan B; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
  • Ju G; Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China.
  • Zhao J; Department of Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • Lin L; Beijing Chao-Yang Hospital, Beijing, China.
  • Yan C; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
  • Liang J; Department of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.
  • Ren X; Department of Oncology, Peking University International Hospital, Beijing, China.
Cell Death Discov ; 9(1): 331, 2023 Sep 04.
Article en En | MEDLINE | ID: mdl-37666810
ABSTRACT
Interferon-gamma (IFN-γ) exerts anti-tumor effects by inducing ferroptosis. Based on CRISPR/Cas9 knockout screening targeting genome-wide protein encoding genes in HepG2 and SK-Hep-1 cell lines, we found that cAMP response element-binding protein (CREB) regulated transcription coactivator 3 (CRTC3) protects tumor cells from drug-induced ferroptosis and significantly inhibits the efficacy of IFN-γ treatment in hepatocellular carcinoma (HCC). Mechanistically, CRTC3 knockout altered tumor cell lipid patterns and increased the abundance of polyunsaturated fatty acids (PUFAs), which enables lipid peroxidation and enhances the susceptibility of HCC cells to ferroptosis inducers. To scavenge for accumulated lipid peroxides (LPO) and maintain redox equilibrium, HCC cells up-regulate SLC7A11 and glutathione peroxidase 4 (GPx4) expressions to enhance the activities of glutamate-cystine antiporter (system xc-) and LPO clearance. As IFN-γ inhibiting system xc-, simultaneous treatment with IFN-γ disrupts the compensatory mechanism, and generates a synergistic effect with CRTC3 knockout to facilitate ferroptosis. Sensitizing effects of CRTC3 depletion were confirmed using typical ferroptosis inducers, including RSL3 and erastin. Sorafeinib, a commonly used target drug in HCC, was repeatedly reported as a ferroptosis inducer. We then conducted both in vitro and vivo experiments and demonstrated that CRTC3 depletion sensitized HCC cells to sorafenib treatment. In conclusion, CRTC3 is involved in the regulation of PUFAs metabolism and ferroptosis. Targeting CRTC3 signaling in combination with ferroptosis inducers present a viable approach for HCC treatment and overcoming drug resistance.

Texto completo: 1 Banco de datos: MEDLINE Tipo de estudio: Diagnostic_studies / Screening_studies Idioma: En Año: 2023 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Tipo de estudio: Diagnostic_studies / Screening_studies Idioma: En Año: 2023 Tipo del documento: Article