Systematic analysis reveals a functional role for STAMBPL1 in the epithelial-mesenchymal transition process across multiple carcinomas
| Autor: | Ting-Ting Yu, Boxi Zhang, Yuqing Hao, Andre Lima Queiroz, Cecilia Lindskog, Amanda Tomie Ouchida, Erik Norberg, Gorbatchev Ambroise, Merve Kacal, Helin Vakifahmetoglu-Norberg |
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| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
Cell biology Epithelial-Mesenchymal Transition Lung Neoplasms Breast Neoplasms Article Deubiquitinating enzyme 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine CRISPR Humans Epithelial–mesenchymal transition Lung cancer Transcription factor Gene knockout 030304 developmental biology Cancer 0303 health sciences biology Deubiquitinating Enzymes medicine.disease Oncology 030220 oncology & carcinogenesis SNAI1 Cancer cell biology.protein Cancer research Female Snail Family Transcription Factors Tumor Suppressor Protein p53 Peptide Hydrolases |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 |
| Popis: | Background Deubiquitinating enzymes (DUBs) are linked to cancer progression and dissemination, yet less is known about their regulation and impact on epithelial–mesenchymal transition (EMT). Methods An integrative translational approach combining systematic computational analyses of The Cancer Genome Atlas cancer cohorts with CRISPR genetics, biochemistry and immunohistochemistry methodologies to identify and assess the role of human DUBs in EMT. Results We identify a previously undiscovered biological function of STAM-binding protein like 1 (STAMBPL1) deubiquitinase in the EMT process in lung and breast carcinomas. We show that STAMBPL1 expression can be regulated by mutant p53 and that its catalytic activity is required to affect the transcription factor SNAI1. Accordingly, genetic depletion and CRISPR-mediated gene knockout of STAMBPL1 leads to marked recovery of epithelial markers, SNAI1 destabilisation and impaired migratory capacity of cancer cells. Reversely, STAMBPL1 expression reprogrammes cells towards a mesenchymal phenotype. A significant STAMBPL1-SNAI1 co-signature was observed across multiple tumour types. Importantly, STAMBPL1 is highly expressed in metastatic tissues compared to matched primary tumour of the same lung cancer patient and its expression predicts poor prognosis. Conclusions Our study provides a novel concept of oncogenic regulation of a DUB and presents a new role and predictive value of STAMBPL1 in the EMT process across multiple carcinomas. |
| Databáze: | OpenAIRE |
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