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Int J Biol Sci 2023; 19(5):1528-1542. doi:10.7150/ijbs.75340 This issue Cite

Research Paper

SIRT7 Downregulation Promotes Breast Cancer Metastasis Via LAP2α-Induced Chromosomal Instability

Qin Huo^#, Siqi Chen^#, Jialang Zhuang, Chuntao Quan, Yue Wang, Ni Xie^✉

Biobank, Department of Laboratory Medicine, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen University, Shenzhen, 518035, China.
^# These authors have contributed equally to this work.

✉ Corresponding author: Ni Xie, Biobank, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen University, China. No. 3002 Sungang West Road, Futian District, Shenzhen 518035, People's Republic of China. Tel: +86 1 350 158 0802; Fax: +86 7 558 300 3435; Email: xn100edu.cn More

Abstract

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 2α (LAP2α) 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 LAP2α 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 LAP2α and SIRT7 knockdown led to increased ubiquitination-dependent degradation of LAP2α and reduced protein levels of LAP2α, whereas LAP2α knockdown did not affect SIRT7 expression. In vitro and in vivo evidence revealed that SIRT7 promotes breast cancer metastasis through the SIRT7/LAP2α axis. In summary, SIRT7 interacts with LAP2α to regulate CIN and metastasis in breast cancer, and inhibition of SIRT7/LAP2α axis represents a potential therapeutic strategy for preventing breast cancer metastasis.

Keywords: SIRT7, chromosomal instability, LAP2α, breast cancer, metastasis

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