KMID : 0620920210530081207
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Experimental & Molecular Medicine 2021 Volume.53 No. 8 p.1207 ~ p.1217
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Histone demethylase KDM4A plays an oncogenic role in nasopharyngeal carcinoma by promoting cell migration and invasion
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Zhao Jingyi
Li Bingyan Ren Yongxia Liang Tiansong Wang Juan Zhai Suna Zhang Xiqian Zhou Pengcheng Yang Daoke Zheng Yingjuan
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Abstract
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Compelling evidence has indicated the vital role of lysine-specific demethylase 4?A (KDM4A), hypoxia-inducible factor-1¥á (HIF1¥á) and the mechanistic target of rapamycin (mTOR) signaling pathway in nasopharyngeal carcinoma (NPC). Therefore, we aimed to investigate whether KDM4A affects NPC progression by regulating the HIF1¥á/DDIT4/mTOR signaling pathway. First, NPC and adjacent tissue samples were collected, and KDM4A protein expression was examined by immunohistochemistry. Then, the interactions among KDM4A, HIF1¥á and DDIT4 were assessed. Gain- and loss-of-function approaches were used to alter KDM4A, HIF1¥á and DDIT4 expression in NPC cells. The mechanism of KDM4A in NPC was evaluated both in vivo and in vitro via RT-qPCR, Western blot analysis, MTT assay, Transwell assay, flow cytometry and tumor formation experiments. KDM4A, HIF1¥á, and DDIT4 were highly expressed in NPC tissues and cells. Mechanistically, KDM4A inhibited the enrichment of histone H3 lysine 9 trimethylation (H3K9me3) in the HIF1¥á promoter region and thus inhibited the methylation of HIF1¥á to promote HIF1¥á expression, thus upregulating DDIT4 and activating the mTOR signaling pathway. Overexpression of KDM4A, HIF1¥á, or DDIT4 or activation of the mTOR signaling pathway promoted SUNE1 cell proliferation, migration, and invasion but inhibited apoptosis. KDM4A silencing blocked the mTOR signaling pathway by inhibiting the HIF1¥á/DDIT4 axis to inhibit the growth of SUNE1 cells in vivo. Collectively, KDM4A silencing could inhibit NPC progression by blocking the activation of the HIF1¥á/DDIT4/mTOR signaling pathway by increasing H3K9me3, highlighting a promising therapeutic target for NPC.
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KEYWORD
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Cancer, Oncogenes
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