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

• Published in: Oncogene 2022-12, Vol.41 (49), p.5223-5237
• Main Authors: Song, Yang-Liu, Yang, Ming-Hui, Zhang, Si, Wang, Hao, Kai, Kun-Lun, Yao, Chun-Xia, Dai, Fei-Fei, Zhou, Meng-Jiao, Li, Jin-Biao, Wei, Zhi-Ru, Yin, Zhongnan, Zhu, Wei-Guo, Xue, Lixiang, Zang, Ming-Xi
• Format: Article
• Language: English
• Subjects: 38/109; 38/89; 631/67/1798; 631/80/304; 64/60; Animals; Apoptosis; Biochemistry; Cell Biology; Cell differentiation; Cell Differentiation - genetics; Cell growth; Cell proliferation; Cell Proliferation - genetics; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic; Epigenetics; Gene expression; Gene silencing; Human Genetics; Internal Medicine; Medicine; Medicine & Public Health; Mice; MicroRNAs; MicroRNAs - metabolism; Molecular biology; Musculoskeletal system; Myoblasts; Myogenesis; Oncology; Polycomb group proteins; Proteins; Rhabdomyosarcoma; Rhabdomyosarcoma - pathology; Rhabdomyosarcoma, Embryonal - pathology; Skeletal muscle; Therapeutic targets; Tumor suppressor genes; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-022-02521-5

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.