SIRT7 Downregulation Promotes Breast Cancer Metastasis Via LAP2?-Induced Chromosomal Instability

Chromosomal instability (CIN) plays an important role in the initiation and progression of carcinomas. However, the regulatory mechanism of metastasis mediated by CIN in breast cancer is not fully understood. Here, we aimed to demonstrate that the deregulation of SIRT7 and lamina-associated polypeptide 2 alpha (LAP2 alpha) critically contributes to CIN-induced metastasis in breast cancer. Expression of SIRT7 and chromosome stability-related genes was examined using western blotting, quantitative real-time PCR, immunohistochemistry, and immunofluorescence; functional significance of SIRT7 was examined using in vitro and in vivo models; and interaction between SIRT7 and LAP2 alpha was assessed by co-inmunoprecipitation (Co-IP) assays. Doxorubicin (DOX) inhibited SIRT7 expression and enhanced CIN in breast cancer cells; SIRT7 deficiency led to CIN in breast cancer cells. Co-IP approach and immunohistochemistry demonstrated that SIRT7 interacted directly and positively with LAP2 alpha and SIRT7 knockdown led to increased ubiquitination-dependent degradation of LAP2 alpha and reduced protein levels of LAP2 alpha, whereas LAP2 alpha knockdown did not affect SIRT7 expression. In vitro and in vivo evidence revealed that SIRT7 promotes breast cancer metastasis through the SIRT7/LAP2 alpha axis. In summary, SIRT7 interacts with LAP2 alpha to regulate CIN and metastasis in breast cancer, and inhibition of SIRT7/LAP2 alpha axis represents a potential therapeutic strategy for preventing breast cancer metastasis.