Sohlh2 suppresses epithelial to mesenchymal transition in breast cancer via downregulation of IL-8

Abstract

Breast cancer is one of the deadliest cancers worldwide due to its strong metastasis to other organs. Metastasis of breast cancer involves a complex set of events, including epithelial-mesenchymal transition (EMT) that increases invasiveness of the tumor cells. We previously identified sohlh2 is a tumor suppressor in the pathogenesis of ovarian cancer. However, the functions of sohlh2 in breast cancer cell migration and invasion remain unknown. Here we report a novel sohlh2/IL-8 signaling pathway in the invasive breast cancer. We observed sohlh2 expression was downregulated in the metastatic breast cancer. Ectopic sohlh2 expression in breast cancer cells reduced EMT and inhibited cell migration and invasion in vitro, and metastasis in vivo. Moreover, the depletion of sohlh2 induced the opposite effects to ectopic sohlh2 expression. RNA-Seq data from a sohlh2 knockdown breast cancer cell line showed that after sohlh2 depletion, the mRNA level of interleukin 8 (IL-8) was significantly increased in these cancer cells, which consequently increased secretion of IL-8 protein. Using chromatin immunoprecipitation and reporter assays, we demonstrated that sohlh2 bound to IL-8 promoter and repressed its activities. The enhanced migration and invasion in sohlh2 -ablated MCF-7 cells were blocked by knockdown of IL-8 expression, while exogenous IL-8 neutralized the anti-migratory and invasive activities of sohlh2 in MDA-MB-231cells. Overall, these results demonstrate that sohlh2 functions as a tumor metastasis suppressor via suppressing IL-8 expression in breast cancer.