Abstract
BRCA1-associated protein 1 (BAP1) is a member of the ubiquitin C-terminal hydrolase family of deubiquitinating enzymes and is implicated in transcriptional regulation. The BAP1 gene is mutated in about 10% of patients with ccRCC, the most common form of renal cancer, suggesting that BAP1 is a tumor suppressor. However, whether BAP1 influences the progression of ccRCC tumors expressing wild-type (WT) BAP1 is unclear. Here, we assessed the expression and function of BAP1 using human ccRCC specimens and cell lines. Analysis of datasets in The Cancer Genome Atlas revealed that lower BAP1 expression is correlated with longer overall survival of ccRCC patients. We established human ccRCC cell lines with stable BAP1 knockout and performed multiomic analysis of BAP1-mediated cellular processes. BAP1 knockout downregulated proteins associated with protein synthesis, resulting in decreased cell growth. Importantly, loss of BAP1 decreased the formation of stress fibers and membrane protrusions and induced migration and invasion defects. BAP1 knockout in ccRCC cells also downregulated the expression of transcriptional repressor protein Snail and decreased the activity of Rho family GTPases, promoting the cells to undergo mesenchymal-epithelial transition. Unexpectedly, quantitative proteomics also showed that BAP1 knockout increased expression of several amino acid transporters and multiple tyrosine kinases, including the epidermal growth factor receptor. Overall, our results suggest that BAP1 regulates multiple cellular processes, and we also uncover a new role for BAP1 in controlling mesenchymal-epithelial transition in ccRCC cells.
Highlights
Proteomic analysis revealed that BRCA1-associated protein 1 (BAP1) was involved in cell motility and morphology. Loss of BAP1 promoted Mesenchymal-epithelial Transition (MET) and inhibited cell proliferation
Next-generation sequencing studies have shown that epigenetic modifiers such as protein polybromo-1, SETD2, BAP1, and KDM5C are frequently mutated in Renal cell carcinoma (RCC) and other tumors [13, 25, 47,48,49]
Previous studies have proposed that BAP1 functions as a tumor suppressor [1, 11], but accumulating evidence suggests that it plays a role in promoting cell proliferation [9, 10, 15]
Summary
Lower expression of WT BAP1 was correlated with longer overall survival in ccRCC patients. An increasing number of studies have demonstrated that depletion of BAP1 inhibits the proliferation of various tumorigenic or nontumorigenic cell types [3, 9, 15,16,17], and germline mutation or low expression of BAP1 correlates with long-term survival of patients with mesothelioma [18, 19] These results suggest that BAP1 plays context-specific roles in cancer progression. Functional assessment confirmed that BAP1 KO inhibited the growth, altered the morphology, and reduced the migration and invasion of ccRCC cells These results provide a comprehensive view of BAP1-mediated cellular processes in ccRCC and reveal that it plays essential roles in cytoskeletal remodeling
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
