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.

令人信服的证据表明赖氨酸特异性去甲基酶 4 A (KDM4A)、缺氧诱导因子 1α (HIF1α) 和雷帕霉素 (mTOR) 信号通路的机制靶标在鼻咽癌 (NPC) 中发挥重要作用。因此，我们的目的是研究KDM4A是否通过调节HIF1α/DDIT4/mTOR信号通路影响NPC进展。首先收集鼻咽癌及癌旁组织样本，采用免疫组化法检测KDM4A蛋白表达。然后，评估 KDM4A、HIF1α 和 DDIT4 之间的相互作用。使用功能获得和丧失的方法来改变 NPC 细胞中的 KDM4A、HIF1α 和 DDIT4 表达。通过 RT-qPCR、Western blot 分析、MTT 测定、Transwell 测定、流式细胞术和肿瘤形成实验在体内和体外评估 KDM4A 在 NPC 中的作用机制。 KDM4A、HIF1α和DDIT4在鼻咽癌组织和细胞中高表达。机制上，KDM4A抑制HIF1α启动子区组蛋白H3赖氨酸9三甲基化（H3K9me3）的富集，从而抑制HIF1α甲基化促进HIF1α表达，从而上调DDIT4并激活mTOR信号通路。 KDM4A、HIF1α或DDIT4的过度表达或mTOR信号通路的激活促进SUNE1细胞增殖、迁移和侵袭，但抑制细胞凋亡。 KDM4A沉默通过抑制HIF1α/DDIT4轴阻断mTOR信号通路从而抑制体内SUNE1细胞的生长。总的来说，KDM4A 沉默可以通过增加 H3K9me3 来阻断 HIF1α/DDIT4/mTOR 信号通路的激活，从而抑制鼻咽癌的进展，这突显了鼻咽癌的一个有前途的治疗靶点。