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EZH2 inhibition sensitizes MYC-high medulloblastoma cancers to PARP inhibition by regulating NUPR1-mediated DNA repair

Oncogene volume 44, pages 391–405 (2025)Cite this article

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Abstract

MYC-driven medulloblastomas (MB) are highly aggressive pediatric brain tumors with poor outcomes, and effective therapies remain limited despite intensive multimodal treatments. Targeting MYC directly is challenging, but exploiting MYC-mediated synthetic lethality holds promise. In this study, we investigated the combined effects of EZH2 and PARP inhibitors in MYC-high medulloblastoma and demonstrated that EZH2 inhibition significantly increased the sensitivity of MYC-high MB tumor cells to PARP inhibitors. This effect occurs through the upregulation of NUPR1, which promotes error-prone non-homologous end-joining (NHEJ) DNA repair by facilitating the recruitment of the XRCC4-LIG4 complex to DNA damage sites. This amplification of error-prone NHEJ DNA repair leads to genetic instability and eventual cell death in cells treated with the PARP inhibitor. The synergistic effect of EZH2 and PARP inhibitors was further validated in both in vitro and in vivo MB models without observed toxicity. These findings reveal a novel therapeutic strategy for MYC-high MB by co-targeting EZH2 and PARP, suggesting that this combination could potentially overcome the clinical challenges associated with this aggressive tumor subtype and warrants further investigation in clinical trials.

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Fig. 1: EZH2 inhibitor sensitizes MYC-high cells to a PARP inhibitor.
Fig. 2: MYC-dependent NUPR1 upregulation mediated by EZH2 inhibitor.
Fig. 3: EZH2 inhibition increases NHEJ activity in MYC-high cells.
Fig. 4: NUPR1 determines the sensitization of MYC-high cells to PARP and EZH2 inhibitors.
Fig. 5: NUPR1 interacts directly with XLF.
Fig. 6: Enhanced inhibition of MYC-high tumor growth with combined EZH2 and PARP inhibitor treatment in vivo.

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Data availability

The differentially expressed genes (DEGs) from the RNA-seq reported in this paper are provided in the supplementary files. The NCI-60 transcriptome database, utilized for analyzing gene expression correlations, was sourced from CellMinerCDB (https://discover.nci.nih.gov/rsconnect/cellminercdb/).

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Acknowledgements

We would like to thank Yachao Liu from the ShanghaiTech University for his assistance with the reagents and plasmids essential for generating our stable cell lines.

Funding

This research was supported by the National Natural Science Foundation of China (82103123), the China Postdoctoral Science Foundation (2021M703208), and the Cyrus Tang Foundation (No. ZSBK0070).

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Author notes

  1. These authors contributed equally: Jianzhong Yu, Jichang Han.

Authors and Affiliations

  1. Department of Neurosurgery, Children’s Hospital of Fudan University, Shanghai, China

    Jianzhong Yu, Huanwen Rui & Hao Li

  2. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

    Jichang Han & Meng Yu

  3. Department of Neurosurgery, Huashan Hospital of Fudan University, Shanghai, China

    An Sun

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Contributions

Jianzhong Yu: writing – original draft, methodology, investigation, formal analysis, data curation. Jichang Han: writing – original draft, formal analysis, visualization, project administration, funding acquisition, conceptualization. Meng Yu: methodology, investigation, formal analysis. Huanwen Rui: methodology, validation. An Sun: resources, supervision. Hao Li: writing – review & editing, funding acquisition, conceptualization, supervision.

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Correspondence to Jichang Han, An Sun or Hao Li.

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MB tissue specimens were obtained from the Children’s Hospital of Fudan University after approval by the ethics review board of the hospital. All patients were informed, and consent was obtained. All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the Children’s Hospital of Fudan University.

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Yu, J., Han, J., Yu, M. et al. EZH2 inhibition sensitizes MYC-high medulloblastoma cancers to PARP inhibition by regulating NUPR1-mediated DNA repair. Oncogene 44, 391–405 (2025). https://doi.org/10.1038/s41388-024-03232-9

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