Abstract
Compelling evidence has indicated the vital role of lysine-specific demethylase 4 A (KDM4A), hypoxia-inducible factor-1α (HIF1α) 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 HIF1α/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, HIF1α and DDIT4 were assessed. Gain- and loss-of-function approaches were used to alter KDM4A, HIF1α 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, HIF1α, and DDIT4 were highly expressed in NPC tissues and cells. Mechanistically, KDM4A inhibited the enrichment of histone H3 lysine 9 trimethylation (H3K9me3) in the HIF1α promoter region and thus inhibited the methylation of HIF1α to promote HIF1α expression, thus upregulating DDIT4 and activating the mTOR signaling pathway. Overexpression of KDM4A, HIF1α, 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 HIF1α/DDIT4 axis to inhibit the growth of SUNE1 cells in vivo. Collectively, KDM4A silencing could inhibit NPC progression by blocking the activation of the HIF1α/DDIT4/mTOR signaling pathway by increasing H3K9me3, highlighting a promising therapeutic target for NPC.
Highlights
Human nasopharyngeal carcinoma (NPC) is a common head and neck malignancy and the common primary malignant tumor arising in the nasopharynx; it has an especially high incidence in Southeast Asia and South China[1,2]
RTqPCR and Western blot analysis revealed that the mRNA (Fig. 1b) and protein (Fig. 1c) expression levels of known as lysine-specific demethylase 4 A (KDM4A) were much higher in NPC tissues than in adjacent tissues
reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis showed that compared with the NP69 cell line, KDM4A was expressed at a higher level in four NPC cell lines (SUNE1, SUNE-2, 5–8 F and 6–10B); of these cell lines, SUNE1 cells exhibited the highest KDM4A expression and were selected for subsequent experiments (Fig. 1d, e)
Summary
Human nasopharyngeal carcinoma (NPC) is a common head and neck malignancy and the common primary malignant tumor arising in the nasopharynx; it has an especially high incidence in Southeast Asia and South China[1,2]. The etiology of NPC is unclear, but the disease is related to Epstein-Barr virus and human papilloma virus infections, and immune factors play a role in its carcinogenesis[3]. Histone demethylase jumonji C domain 2 A (JMJD2A), known as lysine-specific demethylase 4 A (KDM4A), is a potential oncogene and is highly expressed in human tumors[7]. It has been reported that KDM4A plays an important role in the tumorigenesis and progression of NPC, indicating KDM4A as a promising biomarker and target for the treatment of NPC8. KDM4A silencing promotes the accumulation of histone 3 lysine 9 trimethylation (H3K9me3) at the sites of hypoxia-inducible factor-1α (HIF1α), leading to decreased HIF1α mRNA expression and stability[9]
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