NNMT orchestrates the proangiogenic phenotype of cancer-associated fibroblasts via epigenetically regulating ETS2 in oral squamous cell carcinoma

Abstract

Abstract Tumor angiogenesis is pivotal in tumorigenesis and progression. While cancer-associated fibroblasts (CAFs) are known to promote angiogenesis in oral squamous cell carcinoma (OSCC), the underlying mechanisms by which CAFs facilitate angiogenesis within the tumor microenvironment remain elusive. Nicotinamide N'-methyltransferase (NNMT), a member of the N-methyltransferase family, is found to be highly expressed and is identified as a key molecule in the activation of CAFs and the progression of OSCC. Here, combined with our newly established assembled organoid model and fibroblast-endothelial cell (EC) co-culture model, we discovered that stromal NNMT contributed to angiogenesis and tumor growth. Intriguingly, knocking down NNMT in CAFs in OSCC reduced VEGFA expression both in vivo and in vitro. At the molecular level, high expression of NNMT in CAFs promotes ETS2 expression by regulating H3K27 methylation level through mediating methylation deposition. Moreover, ETS2 was furtherly verified to be an activating transcription factor of VEGFA in this study. Collectively, our findings delineated a molecular network in which stromal NNMT initiated an epigenetic reprogramming-ETS2-VEGFA signaling axis, thereby modulating angiogenesis in OSCC.