SENP1 inhibits ferroptosis and promotes head and neck squamous cell carcinoma by regulating ACSL4 protein stability via SUMO1

Xu,Xianzhi; Mao,Yiting; Feng,Zhaowei; Dai,Feng; Gu,Teng; Zheng,Jiwei

doi:10.3892/or.2023.8693

SENP1 inhibits ferroptosis and promotes head and neck squamous cell carcinoma by regulating ACSL4 protein stability via SUMO1

Authors:
- Xianzhi Xu
- Yiting Mao
- Zhaowei Feng
- Feng Dai
- Teng Gu
- Jiwei Zheng
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Affiliations: School of Stomatology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China, Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China, Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
Published online on: December 28, 2023 https://doi.org/10.3892/or.2023.8693
Article Number: 34
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Head and neck squamous cell carcinoma (HNSCC) is currently one of the most common malignancies with a poor prognosis worldwide. Meanwhile, small ubiquitin‑like modifier (SUMO) specific peptidase 1 (SENP1) was associated with ferroptosis. However, the specific functions and underlying mechanisms of action of SENP1 in ferroptosis and tumor progression of HNSCC remain to be established. The findings of the present study implicated a novel ferroptosis pathway in the initiation and progression of HNSCC, providing new functional targets to guide future therapy. In the present study, The Cancer Genome Atlas database was employed to establish a gene model related to ferroptosis and verified SENP1 as a key gene via transcriptome sequencing. Expression of SENP1 in HNSCC tissue and CAL‑27 cells was detected based on reverse transcription‑quantitative PCR and western blot analysis. Proliferation and migration abilities of cells were determined using Cell Counting Kit‑8, wound healing and Transwell experiments. Expression levels of iron, glutathione (GSH) and lipid peroxidation end‑product malondialdehyde (MDA) under conditions of silencing of SENP1 with shRNA lentivirus were assayed. Additionally, the relationship between SENP1 and long‑chain acyl‑coenzyme A synthase 4 (ACSL4) was validated with the aid of immunoblotting and co‑immunoprecipitation (co‑IP). Finally, the influence of shSENP1 on the expression of key ferroptosis proteins, glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11, was evaluated via western blotting. It was revealed that SENP1 was significantly overexpressed in HNSCC and associated with low patient survival. Silencing of SENP1 led to significant suppression of cell proliferation, migration and invasion, increase in the contents of iron ions and MDA and decline in GSH levels in HNSCC cells, thereby enhancing ferroptosis and inhibiting disease progression. Conversely, overexpression of SENP1 suppressed ferroptosis and promoted progression of HNSCC. Co‑IP and western blot analyses revealed a SUMOylation link between SENP1 and ACSL4. SENP1 reduced the stability of ACSL4 protein through deSUMOylation, leading to inhibition of ferroptosis. SENP1 silencing further inhibited the expression of the key iron death protein, GPX4, to regulate ferroptosis. Taken together, SENP1 deficiency promoted ferroptosis and inhibited tumor progression through reduction of SUMOylation of ACSL4 in HNSCC. The collective results of the present study supported the utility of SENP1 as an effective predictive biomarker for targeted treatment of HNSCC.

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