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

Abstract

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.

NNMT/1‐MNA Promote Cell‐Cycle Progression of Breast Cancer by Targeting UBC12/Cullin‐1‐Mediated Degradation of P27 Proteins

“…[17,18] More recently, Joana et al reported that NNMT sustains a core epigenetic program that promotes metastatic colonization in breast cancer. [44] Our current study revealed that NNMT is a critical promoter of breast cancer cell proliferation and cell cycle progression, providing additional evidence for the role of NNMT in promoting breast cancer progression.…”

Molecular, Cellular, and Technical Aspects of Breast Cancer Cell Lines as a Foundational Tool in Cancer Research

“…Other methyltransferases can impact epigenetics by either altering the concentration of the methyl donors or creating a metabolic methylation sink. An example of this is the enzyme Nicotinamide N-methyltransferase (NNMT) which promotes epigenetic remodeling in breast cancer and affects all other NAD+ dependent enzymes such as poly-ADP ribose polymerases (PARPs) and sirtuins [10,11]. In addition, research has been performed using combinations of various dietary phytochemicals that induce inhibition of these silencing enzymes to analyze a decrease in the growth of cancerous cell lines [12].…”