SND1, a novel co‐activator of HIF1α, promotes tumor initiation in PyMT‐induced breast tumor

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.