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

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.

• Authors: Chao Jing, Yuansheng Duan, Mengqian Zhou, Kai Yue, Shanshan Zhuo, Xingchen Li, Dandan Liu, Beibei Ye, Qingchuan Lai, Linqi Li, Xiaofeng Yao, Hui Wei, Wenchao Zhang, Yansheng Wu, Xudong Wang
• Journal: Theranostics (Theranostics) Vol. 11 Issue 6 Pg. 2655-2669 ( 2021) ISSN: 1838-7640 [Electronic] Australia
• PMID: 33456565 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• E2F1 Transcription Factor
• E2F1 protein, human
• PSMD14 protein, human
• Pyrrolidinones
• SOX2 protein, human
• SOXB1 Transcription Factors
• Trans-Activators
• acetopyrrothine
• Proto-Oncogene Proteins c-akt
• Deubiquitinating Enzymes
• Proteasome Endopeptidase Complex

Topics

• Animals
• Carcinogenesis (drug effects, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Deubiquitinating Enzymes (genetics)
• Drug Resistance, Neoplasm (drug effects, genetics)
• E2F1 Transcription Factor (genetics)
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Head and Neck Neoplasms (genetics, pathology)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplastic Stem Cells (metabolism, pathology)
• Prognosis
• Proteasome Endopeptidase Complex (genetics)
• Proto-Oncogene Proteins c-akt (genetics)
• Pyrrolidinones (pharmacology)
• SOXB1 Transcription Factors (genetics)
• Squamous Cell Carcinoma of Head and Neck (genetics, pathology)
• Trans-Activators (genetics)
• Ubiquitination (drug effects, genetics)