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

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 (2023). Nicotinamide N-methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer. The EMBO journal, 42(13), e112559. EMBO Press 10.15252/embj.2022112559

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Bräutigam, Konstantin

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1460-2075

Publisher:

EMBO Press

Language:

English

Submitter:

Pubmed Import

Date Deposited:

01 Jun 2023 15:51

Last Modified:

30 Jun 2023 00:15

Publisher DOI:

10.15252/embj.2022112559

PubMed ID:

37259596

Uncontrolled Keywords:

NNMT breast cancer collagen colonization metastasis

BORIS DOI:

10.48350/183112

URI:

https://boris.unibe.ch/id/eprint/183112

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