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Runx3 is required for oncogenic Myc upregulation in p53-deficient osteosarcoma

Abstract

Osteosarcoma (OS) in human patients is characterized by genetic alteration of TP53. Osteoprogenitor-specific p53-deleted mice (OS mice) have been widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms responsible for the development of OS upon p53 inactivation remain largely unknown. In this study, we detected prominent RUNX3/Runx3 expression in human and mouse p53-deficient OS. Myc was aberrantly upregulated by Runx3 via mR1, a consensus Runx site in the Myc promoter, in a manner dependent on p53 deficiency. Reduction of the Myc level by disruption of mR1 or Runx3 knockdown decreased the tumorigenicity of p53-deficient OS cells and effectively suppressed OS development in OS mice. Furthermore, Runx inhibitors exerted therapeutic effects on OS mice. Together, these results show that p53 deficiency promotes osteosarcomagenesis in human and mouse by allowing Runx3 to induce oncogenic Myc expression.

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Fig. 1: Runx3 is highly upregulated and oncogenic in p53-deficient OS.
Fig. 2: Myc is a positive target of Runx3 in p53-deficient OS.
Fig. 3: mR1 is a responsible element of Myc upregulation by Runx3.
Fig. 4: mR1 and Runx3 are responsible for development of OS in p53-deficient mice.
Fig. 5: Myc induction by Runx3 is dependent on p53-deficiency.

Data availability

All data are available in the main text or the supplementary materials. The ChIP-seq/ATAC-seq and RNA-seq data generated in this study were submitted to DDJB sequence read archive (DRA) with accession numbers DRA009517 and DRA011168, respectively.

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Acknowledgements

We thank G. Huang for critical advice on the study; A. Berns and F. W. Alt for providing the p53 and Myc flox mouse lines, respectively; T. Kishino for generating genome-edited mouse lines; and all members of the Biomedical Research Center, Nagasaki University for maintaining mouse lines. This work was supported by KAKENHI/Japan Society for the Promotion of Science (JSPS) grants 26290040 (KI), 18H02972 (KI), and 19K22724 (KI); by the Funding Program for Next Generation World-Leading Researchers LS097 (KI); and by the JSPS Research Fellowship for Young Scientists 18J20543 (YD).

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KI initiated the study. YD and KI designed the experiments. SO, YD, TU, TI, SK, KO, JT, and KI conducted the experiments. YD performed bioinformatic analyses. IT and TK generated and provided animal materials. SO, YD, and KI wrote the paper. MU and TK coordinated the project. KI supervised the study.

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Correspondence to Kosei Ito.

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Otani, S., Date, Y., Ueno, T. et al. Runx3 is required for oncogenic Myc upregulation in p53-deficient osteosarcoma. Oncogene (2021). https://doi.org/10.1038/s41388-021-02120-w

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