1. Elevated USP9X drives early-to-late-stage oral tumorigenesis via stabilisation of anti-apoptotic MCL-1 protein and impacts outcome in oral cancers.
- Author
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Sulkshane, Prasad, Pawar, Sagar N., Waghole, Rohit, Pawar, Sushil S., Rajput, Priyanka, Uthale, Abhay, Oak, Swapnil, Kalkar, Prajakta, Wani, Harshada, Patil, Rahul, Nair, Sudhir, Rane, Pallavi, and Teni, Tanuja
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PROTEIN metabolism , *PROTEINS , *BIOCHEMISTRY , *RESEARCH , *MOUTH tumors , *ANIMAL experimentation , *RESEARCH methodology , *PROGNOSIS , *MEDICAL cooperation , *EVALUATION research , *PHENOMENOLOGY , *TUMOR classification , *COMPARATIVE studies , *SURVIVAL analysis (Biometry) , *GENES , *ESTERASES , *CELL lines , *SQUAMOUS cell carcinoma , *MICE - Abstract
Background: Overexpression of anti-apoptotic MCL-1 protein in oral squamous cell carcinoma (OSCC) is linked to disease progression, therapy resistance and poor outcome. Despite its characteristic short half-life owing to ubiquitin-proteasome-dependent degradation, oral tumours frequently show elevated MCL-1 protein expression. Hence, we investigated the role of deubiquitinase USP9X in stabilising MCL-1 protein and its contribution to oral tumorigenesis.Methods: Expression of MCL-1 and USP9X was assessed by immunoblotting and immunohistochemistry in oral cancer cell lines and tissues. The association between MCL-1 and USP9X was confirmed by coimmunoprecipitation and immunofluorescence. Cell death assessment was performed by MTT, flow cytometry and clonogenic assays.Results: Both USP9X and MCL-1 are significantly elevated in oral premalignant lesions and oral tumours versus normal mucosa. USP9X interacts with and deubiquitinates MCL-1, thereby stabilising it. Pharmacological inhibition of USP9X potently induced cell death in OSCC cells in vitro and in vivo. The elevated expression of USP9X and MCL-1 correlated with poor prognosis in OSCC patients.Conclusion: We demonstrate the oncogenic role of USP9X in driving early-to-late stages of oral tumorigenesis via stabilisation of MCL-1, suggesting its potential as a prognostic biomarker and therapeutic target in oral cancers. [ABSTRACT FROM AUTHOR]- Published
- 2021
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