PRMT5/Sohlh2/Sirt1 Signaling Pathway in Vascular Endothelial Cells Modulates Lung Metastasis of Triple‐Negative Breast Cancer

ABSTRACT Lung metastasis accounts for the majority of deaths in patients with triple‐negative breast cancer (TNBC). The interaction between tumor cells and vascular endothelial cells (VECs) plays a crucial role during cancer metastasis. Sohlh2 is known as a tumor suppressor gene in the breast cancer progression. However, the role of Sohlh2 in the crosstalk of VECs and tumor cells remain unclear. The results of tissue microarray show that low Sohlh2 expression in VECs is associated with poor prognosis, and metastasis in clinical TNBC patients. Functional studies reveal that overexpression Sohlh2 in VECs could repress the adhesion and trans‐endothelial migration of TNBC cells, attenuate EC senescence, increased permeability, and inflammation induced by TNBC cells. Endothelial cell‐specific knock in Sohlh2 suppresses TNBC lung metastasis. Moreover, mechanism studies show that Sohlh2 represses NF‐κB signaling pathway activation by promoting Sirt1 transcription in VECs. PRMT5‐mediated Sohlh2 arginine methylation promotes the CUL4B‐mediated ubiquitylation and degradation of Sohlh2, leading to the inhibition of Sohlh2 effects in VECs. Taken together, these findings demonstrate that PRMT5/Sohlh2/Sirt1 signaling pathway in VECs plays a critical role in regulating the lung metastasis in TNBC, indicating PRMT5/Sohlh2/Sirt1 signaling as potential targets in the treatment of TNBC metastasis.