Strong evidence has indicated that upregulation of chemokine (CC motif) ligand-2 (CCL2) expression and the presence of an inflammatory tumor microenvironment significantly contribute to the migratory and invasive properties of oral squamous cell carcinoma, specifically oral tongue squamous cell carcinoma (OTSCC). However, the precise epigenetic mechanism responsible for enhanced CCL2 expression in response to the inflammatory mediator tumor necrosis factor alpha (TNF-α) in OTSCC remains inadequately elucidated. We have demonstrated that the production of CCL2 can be induced by TNF-α, and this induction is mediated by the chromatin remodel protein BRG1. Through the use of a chromatin immunoprecipitation (ChIP) assay, we have found that BRG1 was involved in the recruitment of acetylated histones H3 and H4 at the CCL2 promoter, thereby activating TNF-α-induced CCL2 transcription. Furthermore, we have observed that recruitment of NF-κB p65 to the CCL2 promoter was increased following BRG1 overexpression and decreased after BRG1 knockdown in OTSCC cells. Our Re-ChIP assay has shown that BRG1 knockdown completely inhibits the recruitment of both acetylated histone H3 or H4 and NF-κB to the CCL2 promoter. In summary, the findings of our study demonstrate that BRG1 plays a significant role in mediating the production of CCL2 in OTSCC cells in response to TNF-α stimulation. This process involves the cooperative action of acetylated histone and NF-κB recruitment to the CCL2 promoter site. Our data suggest that BRG1 serves as a critical epigenetic mediator in the regulation of TNF-α-induced CCL2 transcription in OTSCC cells.

中文翻译：

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BRG1介导口腔舌鳞状细胞癌细胞中TNFα诱导的CCL2表达的表观遗传调控

强有力的证据表明，趋化因子（CC 基序）配体 2 (CCL2) 表达的上调和炎性肿瘤微环境的存在显着促进口腔鳞状细胞癌，特别是口腔舌鳞状细胞癌 (OTSCC) 的迁移和侵袭特性。 。然而，OTSCC 中 CCL2 表达增强以响应炎症介质肿瘤坏死因子 α (TNF-α) 的精确表观遗传机制仍未得到充分阐明。我们已经证明，TNF-α 可以诱导 CCL2 的产生，并且这种诱导是由染色质重塑蛋白 BRG1 介导的。通过使用染色质免疫沉淀 (ChIP) 测定，我们发现 BRG1 参与CCL2启动子处乙酰化组蛋白 H3 和 H4 的募集，从而激活 TNF-α 诱导的 CCL2 转录。此外，我们观察到在 OTSCC 细胞中，BRG1 过表达后，NF-κB p65 向 CCL2 启动子的募集量增加，而 BRG1 敲低后，NF-κB p65 向 CCL2 启动子的募集量减少。我们的 Re-ChIP 测定表明，BRG1 敲低完全抑制乙酰化组蛋白 H3 或 H4 以及 NF-κB 向 CCL2 启动子的募集。总之，我们的研究结果表明，BRG1 在介导 OTSCC 细胞响应 TNF-α 刺激而产生 CCL2 方面发挥着重要作用。该过程涉及乙酰化组蛋白和 NF-κB 募集到 CCL2 启动子位点的协同作用。我们的数据表明，BRG1 在 OTSCC 细胞中 TNF-α 诱导的 CCL2 转录调节中充当关键的表观遗传介质。