Epigenetic reprogramming underlies efficacy of DNA demethylation therapy in osteosarcomas

Naofumi Asano, Hideyuki Takeshima, Satoshi Yamashita, Hironori Takamatsu, Naoko Hattori, Takashi Kubo, Akihiko Yoshida, Eisuke Kobayashi, Robert Nakayama, Morio Matsumoto, Masaya Nakamura, Hitoshi Ichikawa, Akira Kawai, Tadashi Kondo, Toshikazu Ushijima

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Abstract

Osteosarcoma (OS) patients with metastasis or recurrent tumors still suffer from poor prognosis. Studies have indicated the efficacy of DNA demethylation therapy for OS, but the underlying mechanism is still unclear. Here, we aimed to clarify the mechanism of how epigenetic therapy has therapeutic efficacy in OS. Treatment of four OS cell lines with a DNA demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC) treatment, markedly suppressed their growth, and in vivo efficacy was further confirmed using two OS xenografts. Genome-wide DNA methylation analysis showed that 10 of 28 primary OS had large numbers of methylated CpG islands while the remaining 18 OS did not, clustering together with normal tissue samples and Ewing sarcoma samples. Among the genes aberrantly methylated in primary OS, genes involved in skeletal system morphogenesis were present. Searching for methylation-silenced genes by expression microarray screening of two OS cell lines after 5-aza-dC treatment revealed that multiple tumor-suppressor and osteo/chondrogenesis-related genes were re-activated by 5-aza-dC treatment of OS cells. Simultaneous activation of multiple genes related to osteogenesis and cell proliferation, namely epigenetic reprogramming, was considered to underlie the efficacy of DNA demethylation therapy in OS.

Original languageEnglish
Article number20360
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

ASJC Scopus subject areas

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    Asano, N., Takeshima, H., Yamashita, S., Takamatsu, H., Hattori, N., Kubo, T., Yoshida, A., Kobayashi, E., Nakayama, R., Matsumoto, M., Nakamura, M., Ichikawa, H., Kawai, A., Kondo, T., & Ushijima, T. (2019). Epigenetic reprogramming underlies efficacy of DNA demethylation therapy in osteosarcomas. Scientific reports, 9(1), [20360]. https://doi.org/10.1038/s41598-019-56883-0