Histone demethylase JMJD1C promotes the polarization of M1 macrophages to prevent glioma by upregulating miR-302a.

Chuanhong Zhong,Lilei Peng,Kaiguo Xia,Bei Tao,Xianglong Li,Feilong Yang,Tangming Peng,Ligang Chen,Xiangguo Xia,Xiaobo Yang

doi:10.1002/ctm2.424

Abstract

Glioma is regarded as an aggressive lethal primary brain tumor. Jumonji domain containing 1C (JMJD1C) is a H3K9 demethylase which participates in the progression of various tumors, but its specific function and underlying mechanism in glioma development remain undefined, which is the purpose of our work. We initially assessed JMJD1C expression in glioma tissues and cells using the assays of RT‐qPCR and immunohistochemistry. Meanwhile, the H3K9 level at the microRNA (miR)‐302a promoter region was measured by chromatin immunoprecipitation assay, while luciferase‐based reporter assay was performed for validation of the binding affinity between miR‐302a and methyltransferase‐like 3 (METTL3). The effect of METTL3 on suppressor of cytokine signaling 2 (SOCS2) was subsequently analyzed by MeRIP‐RT‐qPCR. Finally, a xenograft tumor model was established in nude mice, followed by measurement of tumor‐associated macrophages using flow cytometry. JMJD1C was poorly expressed in glioma tissues. Furthermore, JMJD1C increased miR‐302a expression through promoting H3K9me1 demethylation at the miR‐302a promoter region. miR‐302a was identified to target METTL3, which could inhibit SOCS2 expression via m6A modification. JMJD1C promoted M1 macrophage polarization and suppressed the growth of glioma xenografts through the miR‐302a/METTL3/SOCS2 axis both in vivo and in vitro. In conclusion, JMJD1C could enhance M1 macrophage polarization to inhibit the onset of glioma, bringing a new insight into the contribution of JMJD1C to the pathobiology of glioma, with possible implications for targeted therapeutic method.

Highlights

Glioma, which is the commonest malignancy appearing in human brain, is an essentially incurable disease.[1]
According to the bioinformatics analysis results, analysis of JMJD1C expression in glioma samples and normal samples collected by TCGA and GTEX using the GEPIA database suggested a decline of JMJD1C expression in glioma samples (Figure S1, Supporting Information)
RTqPCR displayed lower levels of JMJD1C in U251, LN-229, The cell proliferation of LN-229 and U251 cells stably overexpressing JMJD1C was screened by EdU staining and CCK-8 assay, which showed that overexpression of JMJD1C exerted functions on glioma cell proliferation in vitro (Figure 2A,B)

Summary

Introduction

Glioma, which is the commonest malignancy appearing in human brain, is an essentially incurable disease.[1] Among all malignant brain tumors, glioma accounts for 81% of cases, which arises in glial cells.[2] Due to the rapid invasive ability of glioma cells, the mean overall survival of patients with high-grade glioma is only 15 months.[3] it is a matter of urgency to identify new biomarkers for the diagnosis of glioma, which is a challenging goal because of the molecular heterogeneity of the disease.[4] Accumulating epigenetic analyses have revealed that mutant epigenetic modifiers are common in glioma, and it is likely that dysregulated epigenetic mechanisms participate in the formation of glioma.[5] DNA methylation and demethylation, as well as histone methylation are involved in epigenetic modification, as may occur in tumor lines.[6] M1 polarized macrophages are considered to be activated macrophages, which can phagocytose pathogens as part of the innate immune response.[7] the activation of macrophages is closely related to the progression of glioma.[8] In contrast to normal macrophages, tumorassociated macrophages (TAMs) can exacerbate tumor progression to malignancy by promoting angiogenesis, cell invasion, and migration.[9]

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Discussion

Conclusion