Abstract
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.
Highlights
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
We show for the first time that bromodomain and extraterminal domain (BET) inhibitor JQ1 could reduce Il34 expression in two IL-34 highly producing cancer cells, such as OV3121ras4 and HM-1
BET inhibitor JQ1 suppresses IL-34 expression in IL-34producing cancer cell lines In order to find possible candidates that could regulate IL-34 expression, we have at first taken a glance at transcriptional changes of IL34 in human cancer cell lines and a tumor tissue treated with several low molecular inhibitors
Summary
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. It has been reported that the macrophages generated by stimulation through CSF-1R signaling have the potential to induce T cell exhaustion and dysfunction [12]. There is another clinical fact that IL-34 expression in cancer correlates with poor prognosis and higher disease stage in several types of cancers such as brain, lung, ovarian cancers, and melanoma [13]. This study aims to clarify the transcriptional regulator that controls Il34 expression
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