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C/ebpα represses the oncogenic Runx3–Myc axis in p53-deficient osteosarcoma development

Oncogene volume 42, pages 2485–2494 (2023)Cite this article

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Abstract

Osteosarcoma (OS) is characterized by TP53 mutations in humans. In mice, loss of p53 triggers OS development, and osteoprogenitor-specific p53-deleted mice are widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms underlying the initiation or progression of OS following or parallel to p53 inactivation remain largely unknown. Here, we examined the role of transcription factors involved in adipogenesis (adipo-TFs) in p53-deficient OS and identified a novel tumor suppressive molecular mechanism mediated by C/ebpα. C/ebpα specifically interacts with Runx3, a p53 deficiency-dependent oncogene, and, in the same manner as p53, decreases the activity of the oncogenic axis of OS, Runx3-Myc, by inhibiting Runx3 DNA binding. The identification of a novel molecular role for C/ebpα in p53-deficient osteosarcomagenesis underscores the importance of the Runx-Myc oncogenic axis as a therapeutic target for OS.

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Fig. 1: C/ebpα is downregulated in p53-deficient osteosarcomagenesis and is a favorable prognostic factor in OS.
Fig. 2: C/ebpα is a tumor suppressor in p53-deficient OS.
Fig. 3: C/ebpα deletion upregulates Myc and enhances the tumorigenicity of p53-deficient MSCs (OS MSCs).
Fig. 4: C/ebpα decreases the DNA binding of Runx3 to mR1 in the absence of p53.
Fig. 5: C/ebpα deletion does not affect Myc expression and osteosarcomagenesis in the presence of p53.
Fig. 6: Runx inhibitors have therapeutic effects on p53- and C/ebpα-deficient OS.

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Data availability

The RNA-seq data of MSCs and mOS cells generated in this study were submitted to DDJB sequence read archive with the accession number DRA012931 and are available online.

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Acknowledgements

We thank I. Taniuchi, A. Berns, and F. W. Alt for providing the Runx3, p53, and Myc flox mouse lines, respectively, 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 18H02972 (KI), 19K22724 (K.I), and 21H03113 (KI), and by the Funding Program for Next Generation World-Leading Researchers LS097 (KI).

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  1. These authors contributed equally: Keisuke Omori, Shohei Otani.

Authors and Affiliations

  1. Department of Molecular Bone Biology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan

    Keisuke Omori, Shohei Otani, Yuki Date, Tomoya Ueno, Tomoko Ito & Kosei Ito

  2. Department of Clinical Oral Oncology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan

    Keisuke Omori & Masahiro Umeda

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Contributions

KO and KI initiated the study. KI designed the experiments. KO, SO, YD, TU, TI, and KI conducted the experiments. YD performed bioinformatic analyses. SO and KI wrote the manuscript. MU coordinated the project. KI supervised the study.

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Correspondence to Kosei Ito.

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Omori, K., Otani, S., Date, Y. et al. C/ebpα represses the oncogenic Runx3–Myc axis in p53-deficient osteosarcoma development. Oncogene 42, 2485–2494 (2023). https://doi.org/10.1038/s41388-023-02761-z

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