Bromodomain-containing protein 4 regulates interleukin-34 expression in mouse ovarian cancer cells

Inflammation and Regeneration

Hidefumi Suzuki¹  Hidehisa Takahashi¹  Haruka Wada²  Naoki Hama²  Ken-ichiro Seino²  Delnur Anwar²  Ryo Otsuka²  Takuto Kobayashi²  Muhammad Baghdadi²  Nanumi Han² 

[1] Department of Molecular Biology, School of Medicine, Yokohama City University, 3-9 of Fukuura Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan;Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, 060-0815, Sapporo, Hokkaido, Japan;

关键词: Bromodomain-containing protein 4;    Interleukin-34;    Cytokine induction;    Gene regulation;    JQ1;    Tumor cell biology;    Tumor promotor;   

DOI  :  10.1186/s41232-020-00129-4

来源: Springer

【 摘 要 】

BackgroundInterleukin (IL)-34 acts as an alternative ligand for the colony-stimulating factor-1 receptor and controls the biology of myeloid cells, including survival, proliferation, and differentiation. IL-34 has been reported to be expressed in cancer cells and to promote tumor progression and metastasis of certain cancers via the promotion of angiogenesis and immunosuppressive macrophage differentiation. We have shown in our previous reports that targeting IL-34 in chemo-resistant tumors in vitro resulted in a remarkable inhibition of tumor growth. Also, we reported poor prognosis in patients with IL-34-expressing tumor. Therefore, blocking of IL-34 is considered as a promising therapeutic strategy to suppress tumor progression. However, the molecular mechanisms that control IL-34 production are still largely unknown.MethodsIL-34 producing ovarian cancer cell line HM-1 was treated by bromodomain and extra terminal inhibitor JQ1. The mRNA and protein expression of IL-34 was evaluated after JQ1 treatment. Chromatin immunoprecipitation was performed to confirm the involvement of bromodomain-containing protein 4 (Brd4) in the regulation of the Il34 gene. Anti-tumor effect of JQ1 was evaluated in mouse tumor model.ResultsWe identified Brd4 as one of the critical molecules that regulate Il34 expression in cancer cells. Consistent with this, we found that JQ1 is capable of efficiently suppressing the recruitment of Brd4 to the promotor region of Il34 gene. Additionally, JQ1 treatment of mice bearing IL-34-producing tumor inhibited the tumor growth along with decreasing Il34 expression in the tumor.ConclusionThe results unveiled for the first time the responsible molecule Brd4 that regulates Il34 expression in cancer cells and suggested its possibility as a treatment target.

【 授权许可】

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