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URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers

Author

Listed:
  • Zhiwen Ding

    (Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University)

  • Yufei Pan

    (Naval Medical University)

  • Taiyu Shang

    (Fudan University)

  • Tianyi Jiang

    (Naval Medical University)

  • Yunkai Lin

    (Naval Medical University)

  • Chun Yang

    (Children’s Hospital of Soochow University)

  • Shujie Pang

    (Naval Medical University)

  • Xiaowen Cui

    (Naval Medical University)

  • Yixiu Wang

    (Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University)

  • Xiao fan Feng

    (Naval Medical University)

  • Mengyou Xu

    (Naval Medical University)

  • Mengmiao Pei

    (Naval Medical University)

  • Yibin Chen

    (Naval Medical University)

  • Xin Li

    (Naval Medical University)

  • Jin Ding

    (Naval Medical University)

  • Yexiong Tan

    (Naval Medical University)

  • Hongyang Wang

    (Naval Medical University
    Fudan University)

  • Liwei Dong

    (Naval Medical University)

  • Lu Wang

    (Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University)

Abstract

The clinical benefit of tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) is limited due to drug resistance. Here, we uncover that lipid metabolism reprogramming mediated by unconventional prefoldin RPB5 interactor (URI) endows HCC with resistance to TKIs-induced ferroptosis. Mechanistically, URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2 dependent manner. Importantly, p53 binds to the promoter of stearoyl-CoA desaturase 1 (SCD1) and represses its transcription. High expression of URI is correlated with high level of SCD1 and their synergetic expression predicts poor prognosis and TKIs resistance in HCC. The combination of SCD1 inhibitor aramchol and deuterated sorafenib derivative donafenib displays promising anti-tumor effects in p53-wild type HCC patient-derived organoids and xenografted tumors. This combination therapy has potential clinical benefits for the patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1.

Suggested Citation

  • Zhiwen Ding & Yufei Pan & Taiyu Shang & Tianyi Jiang & Yunkai Lin & Chun Yang & Shujie Pang & Xiaowen Cui & Yixiu Wang & Xiao fan Feng & Mengyou Xu & Mengmiao Pei & Yibin Chen & Xin Li & Jin Ding & Ye, 2023. "URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41852-z
    DOI: 10.1038/s41467-023-41852-z
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    1. Mahmoud Ghandi & Franklin W. Huang & Judit Jané-Valbuena & Gregory V. Kryukov & Christopher C. Lo & E. Robert McDonald & Jordi Barretina & Ellen T. Gelfand & Craig M. Bielski & Haoxin Li & Kevin Hu & , 2019. "Next-generation characterization of the Cancer Cell Line Encyclopedia," Nature, Nature, vol. 569(7757), pages 503-508, May.
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