Hypoxia‐induced SENP3 promotes chemosensitivity and mitochondrial fission via deSUMOylation of Drp1

• Published in: Head & neck 2024-11, Vol.46 (11), p.2776-2788
• Main Authors: Mao, Yuanyuan, Liu, Keyue, Yang, Yaocheng, Liang, Yiran, Gong, ZhaoJian, Wu, Kun
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Hypoxia; Cell Line, Tumor; Cholecystokinin; Cisplatin - pharmacology; cisplatin sensitivity; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; Drp1; Drug Resistance, Neoplasm; Dynamins - genetics; Dynamins - metabolism; Flow cytometry; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; head and neck squamous cell carcinoma; Humans; Hypoxia; Mice; Mitochondria; Mitochondrial Dynamics; SENP3; Squamous Cell Carcinoma of Head and Neck - genetics; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; SUMO protein; Sumoylation
• ISSN: 1043-3074; 1097-0347; 1097-0347
• DOI: 10.1002/hed.27821

Objective The study aimed to investigate the effect of the SUMOylation status of Drp1 on mitochondrial fission in CDDP‐treated HNSCC cells cultured under hypoxic conditions. Materials and methods The effect of hypoxia on the chemosensitivity of HNCC cells was evaluated by flow cytometry and CCK‐8 assays. The biological function of SUMO‐specific peptidase 3 (SENP3) was evaluated by loss‐of‐function assays both in vitro and in vivo. SENP3‐regulated deSUMOylation of Drp1 were performed with co‐IP assays. Results SENP3 expression correlated with chemosensitivity in clinical HNSCC samples subjected to hypoxic conditions. Hypoxia‐induced ROS increased HIF‐1α/SENP3 expression and mitochondrial fission in CDDP‐treated HNSCC cells, and these effects were reversed by NAC treatment. SENP3 knockdown reversed hypoxia‐induced mitochondrial fission and inhibited HNSCC cell apoptosis, which decreased CDDP sensitivity. Furthermore, hypoxia‐induced SENP3 deconjugated SUMO2 from Drp1. Conclusion Our findings revealed that hypoxia‐induced SENP3 facilitates CDDP sensitivity and mitochondrial fission via deSUMOylation of Drp1.