多功能蛋白质葡萄球菌核酸酶结构域蛋白1 (staphylococcal nuclease domain-containing protein 1, SND1) 在肿瘤发展的多个方面如增殖、上皮间质转化和免疫逃避中被保守并有所涉及。尽管如此，SND1 在乳腺肿瘤的发生和转移中的确切作用还未被充分探索。在本研究中，我们利用由多瘤病毒中间T抗原 (polyomavirus middle T antigen, PyMT) 引发的小鼠乳腺肿瘤模型，证明了SND1基因敲除明显延缓了由PyMT引发的原发性乳腺肿瘤的发生。通过组织学染色和细胞分析，证实了SND1缺失后肿瘤起始细胞和肺转移的减少。此外，我们的研究结果表明，而MADS-盒转录因子增强者EZH2, 一种与PyMT诱导的乳腺肿瘤密切相关的关键表观遗传修饰酶，作为SND1促进原发性乳腺肿瘤形成的重要介导因子。机制研究发现，SND1在基因转录和启动等方面起着基本的作用，作为缺氧诱导因子1α (hypoxia inducible factor 1 subunit alpha, HIF1α) 的转录辅激活动因子，调节下游靶基因EZH2的表达，促进肿瘤发生。总体而言，本研究提供了关于SND1作为HIF1α的转录辅激活因子加速PyMT诱导的自发性乳腺肿瘤形成，并通过促进EZH2的转录所起到作用的新洞察。该研究为SND1与肿瘤起始细胞形成之间的关系提供了新的认识。©2023 欧洲生化学联合会

The multifunctional protein staphylococcal nuclease domain-containing protein 1 (SND1) is conserved and has been implicated in several aspects of tumor development, such as proliferation, epithelial-mesenchymal transition, and immune evasion. Despite this, the precise role of SND1 in the initiation and metastasis of mammary gland tumors remains largely unexplored. In this study, we utilized a mouse model of breast tumors induced by polyomavirus middle T antigen (PyMT) to demonstrate that the knockout of SND1 significantly delayed the onset of primary mammary tumor formation induced by PyMT. Histological staining and cytometric analysis were conducted to confirm the reduction of tumor-initiating cells and lung metastasis following depletion of SND1. Additionally, our findings demonstrate that enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), a crucial epigenetic modifier implicated in PyMT-induced breast tumors, serves as an essential mediator of SND1-promoted primary mammary tumor formation. Mechanistic investigations revealed that SND1 functions as a transcriptional co-activator of hypoxia inducible factor 1 subunit alpha (HIF1α), thereby regulating the downstream target gene EZH2 and promoting tumorigenesis. Overall, this study provides novel insights into the role of SND1 as a co-activator of HIF1α in the acceleration of PyMT-induced spontaneous breast tumor formation through the promotion of EZH2 transcription. The findings provide novel insights into the relationship between SND1 and the formation of tumor-initiating cells.© 2023 Federation of European Biochemical Societies.