Nicotinamide N‐methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer

• Published in: The EMBO journal 2023-07, Vol.42 (13), p.e112559-n/a
• Main Authors: Couto, Joana Pinto, Vulin, Milica, Jehanno, Charly, Coissieux, Marie‐May, Hamelin, Baptiste, Schmidt, Alexander, Ivanek, Robert, Sethi, Atul, Bräutigam, Konstantin, Frei, Anja L, Hager, Carolina, Manivannan, Madhuri, Gómez‐Miragaya, Jorge, Obradović, Milan MS, Varga, Zsuzsanna, Koelzer, Viktor H, Mertz, Kirsten D, Bentires‐Alj, Mohamed
• Format: Article
• Language: English
• Subjects: Ablation; Adenosylmethionine; Animal models; Animals; Breast cancer; Collagen; Collagen (type I); Colonization; Deoxyribonucleic acid; Depletion; DNA; DNA Methylation; EMBO03; EMBO09; EMBO21; Enzymes; Epigenesis, Genetic; Epigenetics; Extracellular matrix; Genes; Histones; Life Sciences; Metabolism; Metastases; Metastasis; Methyltransferase; Mice; Neoplasms - metabolism; Nicotinamide; Nicotinamide N-Methyltransferase - genetics; Nicotinamide N-Methyltransferase - metabolism; NNMT; Organs; Overflow; Plastic properties; Plasticity; Tumor cells; Tumors; Xenotransplantation
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2022112559

Metastatic colonization of distant organs accounts for over 90% of deaths related to solid cancers, yet the molecular determinants of metastasis remain poorly understood. Here, we unveil a mechanism of colonization in the aggressive basal‐like subtype of breast cancer that is driven by the NAD + metabolic enzyme nicotinamide N‐methyltransferase (NNMT). We demonstrate that NNMT imprints a basal genetic program into cancer cells, enhancing their plasticity. In line, NNMT expression is associated with poor clinical outcomes in patients with breast cancer. Accordingly, ablation of NNMT dramatically suppresses metastasis formation in pre‐clinical mouse models. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation (H3K9me3) and DNA methylation at the promoters of PR/SET Domain‐5 (PRDM5) and extracellular matrix‐related genes. PRDM5 emerged in this study as a pro‐metastatic gene acting via induction of cancer‐cell intrinsic transcription of collagens. Depletion of PRDM5 in tumor cells decreases COL1A1 deposition and impairs metastatic colonization of the lungs. These findings reveal a critical activity of the NNMT‐PRDM5‐COL1A1 axis for cancer cell plasticity and metastasis in basal‐like breast cancer. Synopsis The molecular basis for metastatic colonization of distant organs remains incompletely understood. This study uncovers a critical role for NAD + metabolic enzyme nicotinamide N‐methyltransferase (NNMT) in driving cancer cell plasticity and extracellular matrix remodeling in basal‐like breast cancer. NNMT promotes metastatic colonization and predicts poor survival in breast cancer patients. NNMT enhances tumor initiation and stemness of breast cancer in xenografts. NNMT ablation elevates the pool of the methyl donor S‐adenosylmethionine (SAM), specifically increasing DNA and H3K9 histone methylation. NNMT ablation promotes the epigenetic silencing of collagens, collagen‐processing genes, and the transcriptional regulator PRDM5. Cancer‐cell intrinsic expression of PRDM5 and COL1A1 promotes metastatic colonization. Graphical Abstract An NNMT‐PRDM5‐COL1A1 axis promotes cancer cell plasticity and metastasis in basal‐like breast cancer.