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Acetylation-dependent regulation of core spliceosome modulates hepatocellular carcinoma cassette exons and sensitivity to PARP inhibitors

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  • Linmao Sun

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Yufeng Liu

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Xinyu Guo

    (Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery)

  • Tianming Cui

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Chenghui Wu

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery)

  • Jie Tao

    (Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery)

  • Cheng Cheng

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery)

  • Qi Chu

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery)

  • Changyong Ji

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery)

  • Xianying Li

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery)

  • Hongrui Guo

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Shuhang Liang

    (Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
    University of Science and Technology of China)

  • Huanran Zhou

    (Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
    University of Science and Technology of China)

  • Shuo Zhou

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery)

  • Kun Ma

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Ning Zhang

    (Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery)

  • Jiabei Wang

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Yao Liu

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

  • Lianxin Liu

    (University of Science and Technology of China
    Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery
    Anhui Provincial Clinical Research Center for Hepatobiliary Diseases)

Abstract

Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.

Suggested Citation

  • Linmao Sun & Yufeng Liu & Xinyu Guo & Tianming Cui & Chenghui Wu & Jie Tao & Cheng Cheng & Qi Chu & Changyong Ji & Xianying Li & Hongrui Guo & Shuhang Liang & Huanran Zhou & Shuo Zhou & Kun Ma & Ning , 2024. "Acetylation-dependent regulation of core spliceosome modulates hepatocellular carcinoma cassette exons and sensitivity to PARP inhibitors," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49573-7
    DOI: 10.1038/s41467-024-49573-7
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    References listed on IDEAS

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