Theranostics 2021; 11(6):2655-2669. doi:10.7150/thno.48375

Research Paper

Blockade of deubiquitinating enzyme PSMD14 overcomes chemoresistance in head and neck squamous cell carcinoma by antagonizing E2F1/Akt/SOX2-mediated stemness

Chao Jing1*, Yuansheng Duan1*, Mengqian Zhou1*, Kai Yue1*, Shanshan Zhuo2*, Xingchen Li1, Dandan Liu1, Beibei Ye1, Qingchuan Lai1, Linqi Li1, Xiaofeng Yao1, Hui Wei3, Wenchao Zhang1, Yansheng Wu1✉, Xudong Wang1✉

1. Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China.
2. Department of Ear, Nose and Throat, Tianjin Hospital, Tianjin 300211, China.
3. Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China.
*These authors contributed equally to this work.

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Citation:
Jing C, Duan Y, Zhou M, Yue K, Zhuo S, Li X, Liu D, Ye B, Lai Q, Li L, Yao X, Wei H, Zhang W, Wu Y, Wang X. Blockade of deubiquitinating enzyme PSMD14 overcomes chemoresistance in head and neck squamous cell carcinoma by antagonizing E2F1/Akt/SOX2-mediated stemness. Theranostics 2021; 11(6):2655-2669. doi:10.7150/thno.48375. Available from https://www.thno.org/v11p2655.htm

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Abstract

Increasing evidence reveals a close relationship between deubiquitinating enzymes (DUBs) and cancer progression. In this study, we attempted to identify the roles and mechanisms of critical DUBs in head and neck squamous cell carcinoma (HNSCC).

Methods: Bioinformatics analysis was performed to screen differentially expressed novel DUBs in HNSCC. Immunohistochemistry assay was used to measure the expression of DUB PSMD14 in HNSCC specimens and adjacent normal tissues. The level of PSMD14 in HNSCC tumorigenesis was investigated using a 4-NQO-induced murine HNSCC model. The function of PSMD14 was determined through loss-of-function assays. Chromatin immunoprecipitation, immunoprecipitation and in vivo ubiquitination assay were conducted to explore the potential mechanism of PSMD14. The anti-tumor activity of PSMD14 inhibitor Thiolutin was assessed by in vitro and in vivo experiments.

Results: We identified PSMD14 as one of significantly upregulated DUBs in HNSCC tissues. Aberrant expression of PSMD14 was associated with tumorigenesis and malignant progression of HNSCC and further indicated poor prognosis. The results of in vitro and in vivo experiments demonstrated PSMD14 depletion significantly undermined HNSCC growth, chemoresistance and stemness. Mechanically, PSMD14 inhibited the ubiquitination and degradation of E2F1 to improve the activation of Akt pathway and the transcription of SOX2. Furthermore, PSMD14 inhibitor Thiolutin exhibited a potent anti-tumor effect on HNSCC in vivo and in vitro by impairing DUB activity of PSMD14.

Conclusion: Our findings demonstrate the role and mechanism of PSMD14 in HNSCC, and provide a novel and promising target for diagnosis and clinical therapy of HNSCC.

Keywords: Head and neck squamous cell carcinoma, PSMD14, E2F1, Chemoresistance, Thiolutin