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A GRIP-1–EZH2 switch binding to GATA-4 is linked to the genesis of rhabdomyosarcoma through miR-29a

Oncogene volume 41, pages 5223–5237 (2022)Cite this article

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Abstract

Terminal differentiation failure is an important cause of rhabdomyosarcoma genesis, however, little is known about the epigenetic regulation of aberrant myogenic differentiation. Here, we show that GATA-4 recruits polycomb group proteins such as EZH2 to negatively regulate miR-29a in undifferentiated C2C12 myoblast cells, whereas recruitment of GRIP-1 to GATA-4 proteins displaces EZH2, resulting in the activation of miR-29a during myogenic differentiation of C2C12 cells. Moreover, in poorly differentiated rhabdomyosarcoma cells, EZH2 still binds to the miR-29a promoter with GATA-4 to mediate transcriptional repression of miR-29a. Interestingly, once re-differentiation of rhabdomyosarcoma cells toward skeletal muscle, EZH2 was dispelled from miR-29a promoter which is similar to that in myogenic differentiation of C2C12 cells. Eventually, this expression of miR-29a results in limited rhabdomyosarcoma cell proliferation and promotes myogenic differentiation. We thus establish that GATA-4 can function as a molecular switch in the up- and downregulation of miR-29a expression. We also demonstrate that GATA-4 acts as a tumor suppressor in rhabdomyosarcoma partly via miR-29a, which thus provides a potential therapeutic target for rhabdomyosarcoma.

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Fig. 1: GATA-4/polycomb group protein interactions mediate the repression of miR-29a.
Fig. 2: GATA-4 recruits GRIP-1 instead of EZH2 to the miR-29a promoter during myogenic differentiation.
Fig. 3: EZH2 binds the miR-29a promoter to mediate transcriptional repression in RMS.
Fig. 4: miR-29a promotes myogenic differentiation and inhibits cellular proliferation in RMS.
Fig. 5: Displacement of EZH2 binding to the miR-29a promoter by GRIP-1 to activate miR-29a expression during the myogenic differentiation of RMS cells.
Fig. 6: GATA-4 functions as a tumor suppressor in RMS.
Fig. 7: GATA-4 functions as a tumor suppressor partly through the regulation of miR-29a.

Data availability

The source data that support the findings of this study are available in figshare with the identifier https://doi.org/10.6084/m9.figshare.20173850.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 82072975, 81771631, 81672091, and 91749107), the High-Level Talents of Henan Province, particularly the support for the Central Plains Thousand Talents Program, which are the leading talents of Central Plains Basic Research (ZYQR201810120), 2022 Henan Province Science and Technology R&D Program Joint Fund (Cultivation of Superior Disciplines), and the key project of discipline construction of Zhengzhou University in 2020 (XKZDQY202002).

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  1. These authors contributed equally: Yang-Liu Song, Ming-Hui Yang, Si Zhang, Hao Wang.

Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China

    Yang-Liu Song, Ming-Hui Yang, Si Zhang, Kun-Lun Kai, Chun-Xia Yao, Fei-Fei Dai, Meng-Jiao Zhou, Jin-Biao Li & Ming-Xi Zang

  2. Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, China

    Hao Wang, Zhongnan Yin & Lixiang Xue

  3. The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Zhi-Ru Wei

  4. Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China

    Wei-Guo Zhu

  5. Cancer Center of Peking University Third Hospital, Peking University Third Hospital, Beijing, 100191, China

    Lixiang Xue

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Contributions

MXZ, LXX and WGZ conceived, designed, and directed the study. YLS performed most ChIP, GST pull-down, and coimmunoprecipitation experiments. MHY performed real-time PCR and transfection experiments. SZ finishes cell proliferation assay and Xenograft tumor experiment. HW performed immunofluorescence and immunohistochemistry assays. KLK, CXY, FFD, MJZ, JBL, ZRW, and ZNY analyzed data.

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Correspondence to Lixiang Xue or Ming-Xi Zang.

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Song, YL., Yang, MH., Zhang, S. et al. A GRIP-1–EZH2 switch binding to GATA-4 is linked to the genesis of rhabdomyosarcoma through miR-29a. Oncogene 41, 5223–5237 (2022). https://doi.org/10.1038/s41388-022-02521-5

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