SUMOylation of SYNJ2BP-COX16 promotes breast cancer progression through DRP1-mediated mitochondrial fission

• Published in: Cancer letters 2022-10, Vol.547, p.215871-215871, Article 215871
• Main Authors: Wang, Miao, Wei, Ranru, Li, Guohui, Bi, Hai-Lian, Jia, Zhaojun, Zhang, Mengjie, Pang, Mengyao, Li, Xiaona, Ma, Liming, Tang, Ying
• Format: Article
• Language: English
• Subjects: Antibodies; Apoptosis; ATP; Breast cancer; Cell division; Cell growth; Cell proliferation; Cytochrome; Cytochrome-c oxidase; Drug development; Dynamin; Enzymes; Fusion protein; Laboratory animals; Leukemia; Localization; Metastases; Metastasis; Mitochondria; Peptides; Phosphorylation; Plasmids; Proteins; SUMO protein; Tumors; Ubiquitin; Ubiquitin-conjugating enzyme; Wound healing
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.215871

Treatments targeting oncogenic fusion proteins are notable examples of successful drug development. Abnormal splicing of genes resulting in fusion proteins is a critical driver of various tumors, but the underlying mechanism remains poorly understood. Here, we show that SUMOylation of the fusion protein Synaptojanin 2 binding protein-Cytochrome-c oxidase 16 (SYNJ2BP-COX16) at K107 induces mitochondrial fission in breast cancer and that the K107 site regulates SYNJ2BP-COX16 mitochondrial subcellular localization. Compared with a non-SUMOylated K107R mutant, wild-type SYNJ2BP-COX16 contributed to breast cancer cell proliferation and metastasis in vivo and in vitro by increasing adenosine triphosphate (ATP) production and cytochrome-c oxidase (COX) activity. SUMOylated SYNJ2BP-COX16 recruits dynamin-related protein 1 (DRP1) to the mitochondria to promote ubiquitin-conjugating enzyme 9 (UBC9) binding to DRP1, enhance SUMOylation of DRP1 and phosphorylation of DRP1 at S616, and then induce mitochondrial fission. Moreover, Mdivi-1, an inhibitor of DRP1 phosphorylation, decreased the localization of DRP1 in mitochondria, and prevents SYNJ2BP-COX16 induced mitochondrial fission, cell proliferation and metastasis. Based on these data, SYNJ2BP-COX16 promotes breast cancer progression through the phosphorylation of DRP1 and subsequent induction of mitochondrial fission, indicating that SUMOylation at the K107 residue of SYNJ2BP-COX16 is a novel potential treatment target for breast cancer. •SUMOylation regulates mitochondrial fission and cell proliferation and metastasis in breast cancer cells.•SUMOylation regulates mitochondrial subcellular localization of SYNJ2BP-COX16.•SUMOylation of SYNJ2BP-COX16 induces SUMOylation and phosphorylation of DRP1.