Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
Department of Surgery, University Hospital Basel, Basel, Switzerland.
EMBO J. 2023 Jul 3;42(13):e112559. doi: 10.15252/embj.2022112559. Epub 2023 Jun 1.
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.
远处器官的转移定植是导致实体癌症相关死亡的主要原因，超过 90%，但转移的分子决定因素仍知之甚少。在这里，我们揭示了一种在侵袭性基底样乳腺癌亚型中定植的机制，该机制由 NAD 代谢酶烟酰胺 N-甲基转移酶 (NNMT) 驱动。我们证明 NNMT 将基底遗传程序植入癌细胞，增强其可塑性。相应地，NNMT 表达与乳腺癌患者的不良临床结局相关。因此，在临床前小鼠模型中，NNMT 的缺失极大地抑制了转移的形成。在机制上，NNMT 的耗竭导致甲基溢出，增加组蛋白 H3K9 三甲基化 (H3K9me3) 和 PR/SET 域-5 (PRDM5) 启动子以及细胞外基质相关基因的 DNA 甲基化。在这项研究中，PRDM5 作为一种促转移基因出现，通过诱导胶原蛋白的癌症细胞内在转录起作用。肿瘤细胞中 PRDM5 的缺失会减少 COL1A1 的沉积并损害肺转移定植。这些发现揭示了 NNMT-PRDM5-COL1A1 轴在基底样乳腺癌中对癌细胞可塑性和转移的关键作用。
