Bromodomain-containing protein 4 regulates interleukin-34 expression in mouse ovarian cancer cells
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(2020) 40:25
Inflammation and Regeneration
RESEARCH ARTICLE
Open Access
Bromodomain-containing protein 4 regulates interleukin-34 expression in mouse ovarian cancer cells Nanumi Han1†, Delnur Anwar1†, Naoki Hama1, Takuto Kobayashi1, Hidefumi Suzuki2, Hidehisa Takahashi2, Haruka Wada1, Ryo Otsuka1, Muhammad Baghdadi1 and Ken-ichiro Seino1*
Abstract Background: Interleukin (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. Methods: IL-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. Results: We 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. Conclusion: The 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. Keywords: Bromodomain-containing protein 4, Interleukin-34, Cytokine induction, Gene regulation, JQ1, Tumor cell biology, Tumor promotor
Background Tumor microenvironment (TME) is composed of various types of cells including not only tumor cells but also immune cells, fibroblasts, mesenchymal, and endothelial cells. Cytokine is known as one of the important * Correspondence: [email protected] Nanumi Han and Delnur Anwar equally contributed to this work. 1 Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, Hokkaido 060-0815, Japan Full list of author information is available at the end of the article
components for interactions and communications between tumor and non-tumor cells. Some cytokines promote tumor progression while others have anti-tumor effects. For example, interleukin (IL)-10 is involved in suppression of
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