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TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma

Oncogene volume 37, pages 2903–2920 (2018)Cite this article

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Abstract

The tumor microenvironment promotes epigenetic changes in tumor cells associated with tumor aggressiveness. Here we report that in primary tumor cells, increased interleukin-6 (IL-6) expression brought on by DNA demethylation of its promoter by ten-eleven translocation 2 (TET2) promotes lung metastasis in osteosarcoma (OS). Xenograft experiments show increased IL-6 expression and decreased methylation of its promoter in OS cells after implantation relative to before implantation. In addition, changes in IL-6 methylation and expression seen in OS cells at the primary site were maintained at the metastatic site. TET2 knockdown in OS cells suppressed upregulation of IL-6 and demethylation of its promoter in xenograft tumors and decreased tumor metastasis. We also present evidence showing that tumor cell-derived IL-6 facilitates glycolytic metabolism in tumor cells by activating the MEK/ERK1/2/hypoxia-inducible transcription factor-1α (HIF-1α) pathway and increases lung colonization by OS cells by upregulating expression of intercellular adhesion molecule-1 (ICAM-1), enhancing tumor metastasis. Blocking IL-6 signaling with a humanized monoclonal antibody against the IL-6 receptor reduced lung metastasis and prolonged survival of xenografted mice. These findings suggest that TET2-dependent IL-6 induction enables acquisition of aggressive phenotypes in OS cells via the tumor microenvironment and that blocking IL-6 signaling could be serve as a potential therapy to antagonize metastasis.

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Acknowledgements

We thank our colleagues for valuable suggestions and discussion. We also thank K. Tabu, N. Shirai, S. Iwaki, Y. Shogenji, and M. Kamada for technical assistance. This work was supported by the Scientific Research Fund of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (grant 26116722 to YO, grant 15K06836 to TK, grant 17K08663 to ME), and by the Core Research for Evolutional Science and Technology (CREST) program of the Japan Science and Technology Agency (JST) (grant 13417915 to YO) and by the CREST program of the Japan Agency for Medical Research and Development (AMED) (grant 17gm0610007h0005 to YO).

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  1. These authors contributed equally: Hitoshi Itoh, Tsuyoshi Kadomatsu.

Authors and Affiliations

  1. Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Hitoshi Itoh, Tsuyoshi Kadomatsu, Hironori Tanoue, Masaki Yugami, Keishi Miyata, Motoyoshi Endo, Jun Morinaga, Ryoma Kurahashi, Kazutoyo Terada & Yuichi Oike

  2. Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Hitoshi Itoh, Hironori Tanoue, Masaki Yugami & Hiroshi Mizuta

  3. Center for Clinical Research, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Jun Morinaga

  4. Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Jun Morinaga

  5. Department of Orthopedic Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8525, Japan

    Eisuke Kobayashi & Takeshi Miyamoto

  6. Division of Muscloskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Eisuke Kobayashi

  7. Department of Urology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Ryoma Kurahashi

  8. Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan

    Yuichi Oike

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  1. Hitoshi Itoh
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Itoh, H., Kadomatsu, T., Tanoue, H. et al. TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma. Oncogene 37, 2903–2920 (2018). https://doi.org/10.1038/s41388-018-0160-0

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