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Blockade of deubiquitinating enzyme PSMD14 overcomes chemoresistance in head and neck squamous cell carcinoma by antagonizing E2F1/Akt/SOX2-mediated stemness
- Source :
- Theranostics
- Publication Year :
- 2021
- Publisher :
- Ivyspring International Publisher, 2021.
-
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.
- Subjects :
- 0301 basic medicine
Carcinogenesis
Medicine (miscellaneous)
medicine.disease_cause
Deubiquitinating enzyme
Mice
0302 clinical medicine
PSMD14
E2F1
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Mice, Inbred BALB C
Deubiquitinating Enzymes
Prognosis
Pyrrolidinones
Gene Expression Regulation, Neoplastic
Head and Neck Neoplasms
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Chemoresistance
medicine.drug
Research Paper
Proteasome Endopeptidase Complex
Mice, Nude
Biology
03 medical and health sciences
stomatognathic system
Cell Line, Tumor
medicine
otorhinolaryngologic diseases
Animals
Humans
Protein kinase B
neoplasms
PI3K/AKT/mTOR pathway
Cell Proliferation
Squamous Cell Carcinoma of Head and Neck
SOXB1 Transcription Factors
Ubiquitination
Head and neck squamous cell carcinoma
medicine.disease
Thiolutin
Head and neck squamous-cell carcinoma
stomatognathic diseases
030104 developmental biology
Drug Resistance, Neoplasm
Cancer research
biology.protein
Trans-Activators
Chromatin immunoprecipitation
Proto-Oncogene Proteins c-akt
E2F1 Transcription Factor
Subjects
Details
- Language :
- English
- ISSN :
- 18387640
- Volume :
- 11
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....41457b31fc40f3f3f83e381a98fab731