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EZH2 interacts with HP1BP3 to epigenetically activate WNT7B that promotes temozolomide resistance in glioblastoma

Oncogene volume 42, pages 461–470 (2023)Cite this article

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Abstract

Glioblastoma (GBM) is the most lethal primary brain tumor in adults and harbors a subpopulation of glioma stem cells (GSCs). Enhancer of Zeste Homolog 2 (EZH2), a histone lysine methyltransferase, deeply involves in the stemness maintenance of GSC. However, the precise mechanism and therapeutic potential remain elusive. We postulated that the interactome of EZH2 in GSC is unique. Therefore, we performed proteomic and transcriptomic research to unveil the oncogenic mechanism of EZH2. Immunoprecipitation and mass spectrometry were used to identify proteins that co-precipitate with EZH2. We show that EZH2 binds to heterochromatin protein 1 binding protein 3 (HP1BP3) in GSCs and impairs the methylation of H3K9. Overexpression of HP1BP3 enhances the proliferation, self-renewal and temozolomide (TMZ) resistance of GBM cells. Furthermore, EZH2 and HP1BP3 co-activate WNT7B expression thereby increasing TMZ resistance and stemness of GBM cells. Importantly, inhibition of WNT7B autocrine via LGK974 effectively reverses the TMZ resistance. Our work clarifies a new oncogenic mechanism of EZH2 by which it interacts with HP1BP3 and epigenetically activates WNT7B thereby promoting TMZ resistance in GSCs. Our results provide a rationale for targeting WNT/β-catenin pathway as a promising strategy to overcome TMZ resistance in GSCs.

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Fig. 1: EZH2 protein interacts with HP1BP3 in GSC.
Fig. 2: HP1BP3 expression profile and prognostic value in gliomas.
Fig. 3: HP1BP3 promotes the proliferation, stemness, and enhances TMZ resistance of U87MG and GBM22 cells.
Fig. 4: EZH2 and HP1BP3 co-active WNT7B expression.
Fig. 5: WNT7B is epigenetically activated by EZH2 and HP1BP3 via the blockage of H3K9 methylation.
Fig. 6: Pharmacologic inhibition of WNT7B via LGK974 enhances TMZ efficiency.
Fig. 7: Graphical abstract.

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The datasets supporting the results of this article are included within the article and its additional files.

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Funding

This work was supported by grants from National Natural Science Foundation of China (81772682, 81872058 and 82103540), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and the Natural Science Foundation of Jiangsu Province (BK20200124).

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Author notes

  1. These authors contributed equally: Tianfu Yu, Fengqi Zhou, Wei Tian.

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China

    Tianfu Yu, Fengqi Zhou, Wei Tian, Binbin Wang, Yingyi Wang & Junxia Zhang

  2. Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China

    Tianfu Yu

  3. Department of Neurosurgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China

    Ran Xu

  4. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ailiang Zeng

  5. Department of Medicine, and Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Zhijun Zhou & Min Li

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Contributions

Experimental design: JxZ, YyW, and ML. Conduct of experiments: TfY, FqZ, RX, and BbW. Analysis and interpretation of data: TfY, WT, AlZ and ZjZ. Writing of manuscript: TfY and JxZ.

Corresponding authors

Correspondence to Min Li, Yingyi Wang or Junxia Zhang.

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The authors declare no competing interests.

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Animal experiments were approved by the Animal Management Rule of the Chinese Ministry of Health and were performed in accordance with the approved guidelines and experimental protocol of Nanjing Medical University. All animal experiments were in conformity with the Guide for the Care and Use of Laboratory Animals (National Academies Press, 2011).

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Yu, T., Zhou, F., Tian, W. et al. EZH2 interacts with HP1BP3 to epigenetically activate WNT7B that promotes temozolomide resistance in glioblastoma. Oncogene 42, 461–470 (2023). https://doi.org/10.1038/s41388-022-02570-w

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