Abstract 5379: NNMT loss drives prostate cancer progression through epigenetic and metabolic reprogramming

Abstract Changes in the methylation of proteins, nucleic acids, and metabolites are fundamental in cancer development. Specifically, when these changes affect the methylation of histones and nucleic acids, they can alter the epigenetic status of cells, impacting the expression of thousands of genes and driving cancer initiation and progression. S-adenosylmethionine (SAM) is the universal methyl donor for SAM-dependent reactions, while its byproduct, S-adenosylhomocysteine (SAH), inhibits methyltransferases, including HMTase and DNMTs. Dysregulation of SAM, SAH, and their ratio can reshape the histone and DNA methylation landscape and alter gene expression. Nicotinamide (NAM) N-methyltransferase (NNMT), a one-carbon group methyltransferase that catalyzes NAM methylation to produce SAH and 1-methylnicotinamide (1-MNAM), is a well-characterized methyl sink that reduces the overall methylation potential of cells. NNMT has been implicated in regulating multiple metabolic pathways in cancer cells through its high consumption of SAM and generation of the chemically inert metabolite 1-MNAM. High expression of NNMT in certain cancers, particularly in cancer-associated fibroblasts, results in excessive consumption of the SAM pool (a “SAM-sink”), thereby diverting SAM from DNA and histone methylation processes and ultimately leading to metastasis and cancer progression. Here, we hypothesized that NNMT could act as a tumor suppressor in prostate cancer (PCa), which relies on high SAM availability for polyamine synthesis and methylation. To test this hypothesis, we generated prostate-specific NNMT knockout mice combined with PTEN deletion developed infiltrating carcinoma associated with increased histone methylation marks (H3K36me3/H3K27me3) and activation of oncogenic pathways. Importantly, we identified a recurrent, focal genomic deletion of NNMT in up to 8% of human PCa. Additionally, a tissue microarray containing hundreds of PCa samples demonstrated tumor-specific loss of NNMT expression. CRISPR-mediated NNMT deletion or overexpression in PCa cells caused reciprocal changes in SAM/SAH ratios, global methylation patterns, methylated chromatin marks, and tumor growth in vivo. Importantly, reducing methionine levels, a precursor of SAM, through a methionine-restricted diet resulted in tumor growth inhibition in the context of NNMT activity in multiple cancer models. Together, our data suggest that tumor-specific genetic and epigenetic loss of NNMT results in sufficient SAM availability for DNA and histone methylation, even in nutrient-deprived environments, promoting epigenetic homeostasis and cancer progression. Citation Format: Erick L. Mitchell-Velasquez, Qu Deng, Mohammed Alhusayan, Ramakrishnan Natesan, Sharan Venkatesh, Gabriel Raytsis, Priti Lal, Rahul Mannan, Benjamin Garcia, Irfan Asangani. NNMT loss drives prostate cancer progression through epigenetic and metabolic reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5379.