Elevated USP9X drives early-to-late-stage oral tumorigenesis via stabilisation of anti-apoptotic MCL-1 protein and impacts outcome in oral cancers.

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.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.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.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.
Mesh Terms:
Animals, Carcinoma, Squamous Cell, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Mouth Neoplasms, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Staging, Neoplasm Transplantation, Prognosis, Protein Stability, Survival Analysis, Ubiquitin Thiolesterase, Ubiquitination, Up-Regulation
Br J Cancer
Date: Dec. 01, 2020
Download Curated Data For This Publication
232579
Switch View:
  • Interactions 2