已知癌症相关成纤维细胞 (CAF) 可以促进口腔鳞状细胞癌 (OSCC) 的血管生成。然而，CAF 在肿瘤微环境中促进血管生成的表观遗传机制仍不清楚。烟酰胺 N'-甲基转移酶 (NNMT) 是 N-甲基转移酶家族的成员，被发现是 CAF 激活的关键分子。这项研究表明，成纤维细胞中的 NNMT 通过 OSCC 中的表观遗传重编程 - ETS2-VEGFA 信号轴促进血管生成和肿瘤生长。单细胞RNA测序（scRNA-seq）分析表明，NNMT主要在头颈鳞状细胞癌（HNSCC）的成纤维细胞中高表达。此外，对TCGA数据库的分析和临床样本的多重免疫组化染色也发现NNMT与肿瘤血管生成之间呈正相关。本研究进一步采用组装的类器官模型和成纤维细胞-内皮细胞共培养模型来验证 NNMT 的促血管生成能力。在分子水平上，发现CAF中NNMT的高表达通过介导甲基化沉积来调节H3K27甲基化水平，从而促进ETS2的表达。此外，本研究还证实ETS2是VEGFA的激活转录因子。总的来说，我们的研究结果描绘了血管生成的表观遗传分子调控网络，并为探索 OSCC 的新靶点和临床策略提供了理论基础。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Cancer-associated fibroblasts (CAFs) are known to promote angiogenesis in oral squamous cell carcinoma (OSCC). However, the epigenetic mechanisms through which CAFs facilitate angiogenesis within the tumor microenvironment are still poorly characterized. Nicotinamide N'-methyltransferase (NNMT), a member of the N-methyltransferase family, was found to be a key molecule in the activation of CAFs. This study shows that NNMT in fibroblasts contributes to angiogenesis and tumor growth through an epigenetic reprogramming-ETS2-VEGFA signaling axis in OSCC. Single-cell RNA Sequencing (scRNA-seq) analysis suggests that NNMT is mainly highly expressed in fibroblasts of head and neck squamous cell carcinoma (HNSCC). Moreover, analysis of the TCGA database and multiple immunohistochemical staining of clinical samples also identified a positive correlation between NNMT and tumor angiogenesis. This research further employed an assembled organoid model and a fibroblast-endothelial cell co-culture model to authenticate the proangiogenic ability of NNMT. At the molecular level, high expression of NNMT in CAFs was found to promote ETS2 expression by regulating H3K27 methylation level through mediating methylation deposition. Furthermore, ETS2 was verified to be an activating transcription factor of VEGFA in this study. Collectively, our findings delineate an epigenetic molecular regulatory network of angiogenesis and provide a theoretical basis for exploring new targets and clinical strategy in OSCC.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.