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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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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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).
The authors declare no competing interests.
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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