Nicotinamide N-Methyltransferase Epigenetically Activates Fibronectin 1 Through H3K9me3 Remodeling in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is among the most prevalent malignancies of the urinary system. Patients with advanced ccRCC have poor clinical outcomes. This study aimed to investigate the role of nicotinamide N-methyltransferase (NNMT) in ccRCC. Multiomics analyses revealed aberrant expression of two enzymes in the nicotinamide metabolic pathway, both of which are associated with poor prognosis, with NNMT exhibiting the most pronounced alteration. NNMT modulation per se induces a malignant phenotype, irrespective of substrate or product supplementation. Mechanistically, using western blotting and chromatin immunoprecipitation assays, we demonstrated that NNMT decreases S-adenosylmethionine, thereby reducing histone H3 lysine 9 trimethylation (H3K9me3) at the fibronectin 1 (FN1) promoter and activating FN1 transcription. Exogenous FN1 rescued the migration and invasion in NNMT knockout cells. In clinical specimens, NNMT expression levels were markedly elevated in tumor tissues and correlated with tumor stage. NNMT inhibitor suppressed FN1 expression and tumor progression both in vitro and in vivo. Collectively, our findings establish NNMT as a pivotal epigenetic regulator that drives ccRCC progression through extracellular matrix remodeling, providing novel early-stage diagnostic and therapeutic strategies for ccRCC.

Keywords

clear cell renal cell carcinoma / fibronectin 1 / metabolism / methylation / nicotinamide N-methyltransferase / therapeutic target

References

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