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Targeting DDX11 promotes PARP inhibitor sensitivity in hepatocellular carcinoma by attenuating BRCA2-RAD51 mediated homologous recombination

Oncogene volume 43, pages 35–46 (2024)Cite this article

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Abstract

Homologous recombination (HR) is a major DNA double-strand break (DSB) repair pathway of clinical interest because of treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). Cooperation between RAD51 and BRCA2 is pivotal for DNA DSB repair, and its dysfunction induces HR deficiency and sensitizes cancer cells to PARPi. The depletion of the DEAD-box protein DDX11 was found to suppress HR in hepatocellular carcinoma (HCC) cells. The HR ability of HCC cells is not always dependent on the DDX11 level because of natural DDX11 mutations. In Huh7 cells, natural DDX11 mutations were detected, increasing the susceptibility of Huh7 cells to olaparib in vitro and in vivo. The HR deficiency of Huh7 cells was restored when CRISPR/Cas9–mediated knock-in genomic editing was used to revert the DDX11 Q238H mutation to wild type. The DDX11 Q238H mutation impeded the phosphorylation of DDX11 by ATM at serine 237, preventing the recruitment of RAD51 to damaged DNA sites by disrupting the interaction between RAD51 and BRCA2. Clinically, a high level of DDX11 correlated with advanced clinical characteristics and a poor prognosis and served as an independent risk factor for overall and disease-free survival in patients with HCC. We propose that HCC with a high level of wild-type DDX11 tends to be more resistant to PARPi because of enhanced recombination repair, and the key mutation of DDX11 (Q238H) is potentially exploitable.

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Fig. 1: DDX11 overexpression in HCCs is positively associated with poor prognoses in HCC patients.
Fig. 2: Wild-type DDX11 promotes HR in HCC cells, and the DDX11 mutation may impair HR in the Huh7 HCC cell line.
Fig. 3: Wild-type DDX11 enhances the resistance of HCC Cells to the PARP inhibitor.
Fig. 4: DDX11 protein Q238H mutation impairs the HR ability of Huh7 cells, inhibiting DNA repair and genome stability.
Fig. 5: DDX11 Q238H mutation enhances olaparib suppression effect on HCC growth in vivo.
Fig. 6: DDX11 Q238H mutation impedes the recruitment of BRCA2 and RAD51 to damaged DNA by disrupting the BRCA2–RAD51 interaction.
Fig. 7: DDX11 Q238H mutation impedes the phosphorylation of DDX11 by ATM at S237, disrupting the interaction of BRCA1 and BARD1.
Fig. 8: The proposed model for DDX11 in the HR repair pathway in HCC.

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All data are available from the authors upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82002104, to KC; 81971329, to XGL), Guangdong Basic and Applied Basic Research Foundation (2019A1515110659 and 2022A1515010191), Key project of universities in Guangdong Province (2022ZDZX2023), Discipline Construction Project of Guangdong Medical University (4SG21008G), Youth Research Project of Guangdong Medical University (GDMUD2022004), Talent Development Foundation of The First Dongguan Affiliated Hospital of Guangdong Medical University (GCC2022007).

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Author notes

  1. These authors contributed equally: Kun Cao, Ruonan Wang, Lianhai Li, Yuting Liao.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, China

    Kun Cao, Lianhai Li, Ruixue Li, Xiuwen Liu, Xing-dong Xiong & Xinguang Liu

  2. Scientific Research Platform Service Management Center, Guangdong Medical University, Dongguan, 523808, China

    Ruonan Wang

  3. Department of Radiotherapy, General Hospital of Southern Theater Command of the Chinese People’s Liberation Army, Guangzhou, 510016, China

    Yuting Liao

  4. Department of Surgery, The Second People’s Hospital of Guangdong Province, Guangzhou, 510317, China

    Xiao Hu

  5. Department of Anesthesiology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China

    Yanjie Wang

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Contributions

KC performed most of the experiments. RNW and LHL performed mouse work and IHC analysis. YTL, XH, RXL and XWL provided technical and data analysis assistance. KC, XDX, YJW and XGL designed and interpreted the experiments and wrote the manuscript; YTL participated in proofreading this manuscript; KC, XDX, YJW and XGL revised the manuscript; XGL conceived and supervised the entire project.

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Correspondence to Kun Cao, Xing-dong Xiong, Yanjie Wang or Xinguang Liu.

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Cao, K., Wang, R., Li, L. et al. Targeting DDX11 promotes PARP inhibitor sensitivity in hepatocellular carcinoma by attenuating BRCA2-RAD51 mediated homologous recombination. Oncogene 43, 35–46 (2024). https://doi.org/10.1038/s41388-023-02898-x

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