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

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.

Discovery of Targets for Immune–Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha

“…To demonstrate the utility of BipotentR using a different input pathway, we identified 14 bipotent TFCRs that simultaneously regulate angiogenesis and immune response (Supplementary Table S5) and 14 TFCRs that regulate evasion of growth suppressors and immune response (Supplementary Table S6), using these pathways as inputs to BipotentR (Methods). This included TBX21 and histone demethylase JMJD1C; whereas TBX21 is known to regulate angiogenesis and Tregs ( 101, 102 ), JMJD1C is known to regulate angiogenesis ( 103–105 ) and can polarize macrophages ( 106 ). We also evaluated bipotent targets for angiogenesis and growth suppressor evasion analogously as was done for immunometabolism targets.…”

JMJD1C promotes smooth muscle cell proliferation by activating glycolysis in pulmonary arterial hypertension

“…However, several contradictory studies have shown an antiproliferative effect of JMJD1C on cancer cells. For example, Zhong et al suggested that JMJD1C blocked cell growth by promoting M1 macrophage polarization in glioma [ 29 ]. We thought that the effect of JMJD1C on cell proliferation might be attributed to different pathological states.…”

Ascorbic acid modulates immune responses through Jumonji‐C domain containing histone demethylases and Ten eleven translocation (TET) methylcytosine dioxygenase

“…Although JMJD1C (Histone demethylase) expression was low in gliomas, JMJD1C promoted demethylation of H3K9me1 at the promoter region of miR‐302a, which boosted miR‐302a expression. [ 69 ] miR‐302a suppressed the activity METTL3 that inhibited the SOCS2 expression via m 6 A modification. [ 69,70 ] As SOCS proteins intercepts interferon‐activated STAT‐mediated signaling, JMJD1C may regulate macrophage polarization by modulating STATs‐mediated signaling.…”