Histone demethylase KDM6B promotes glioma cell proliferation by increasing PDGFRA expression via chromatin loop
1Department of Oncology, Hebei General Hospital, Shijiazhuang, China.
Objectives:
Changes in gene expression pattern play an essential role in promoting the process of cancer. For example, platelet-derived growth factor receptor alpha (PDGFRA) is overexpressed in many cancers, including gliomas. Abnormal histone methylation is a typical characteristics of glioma, and our previous studies have shown that histone lysine demethylase 6B (KDM6B) is involved in glioma development by regulating the expression of specific oncogenes. In this study, the regulatory effect and underlying mechanism of KDM6B on PDGFRA expression were investigated.
Methods:
The expression information of KDM6B and PDGFRA in patients with glioma was analyzed in GEPIA database. The expression or activity of KDM6B was regulated with CRISPR interference/activation (CRISPRi/a) assays, gene knockdown and specific inhibitor. Cell proliferation was determined using cell counting kit assay. Chromatin immunoprecipitation assay (ChIP) and ChIP-loop assays were used to determine the H3K27me3 status in the PDGFRA promoter and DNA-DNA interactions mediated by KDM6B.
Results:
The expression of KDM6B and PDGFRA expression is positively correlated in gliomas. CRISPRi/a assays indicated that KDM6B has a positive regulatory role in PDGFRA expression in glioma cells and can promote glioma cell proliferation. KDM6B knockdown and inhibitor assays further proved that KDM6B promotes PDGFRA expression. ChIP assays indicated KDM6B reduces H3K27me3 level in the PDGFRA promoter. The ChIP-loop assays showed KDM6B increases the formation of chromatin loops, which facilitates the proximity of enhancer and promoter.
Conclusion:
This study reveals a new epigenetic mechanism of PDGFRA overexpression in glioma cells, that is, KDM6B catalyzes the demethylation of H3K27me3 and induces chromatin loop formation to activate PDGFRA expression. This study is of great significance for the understanding of glioma development and the application of new treatment strategies, such as radiation therapy combined with epigenetic therapy.
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