USP22 exerts tumor-suppressive functions in colorectal cancer by decreasing mTOR activity
| Autor: | Xin Wang, Robyn Laura Kosinsky, Luisa Wohn, Florian Wegwitz, Dominik Saul, Maria Zerche, Steven A. Johnsen, Yvonne Begus-Nahrmann |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Carcinogenesis Colorectal cancer Biology medicine.disease_cause Article 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor Gene expression medicine Animals Humans Molecular Biology PI3K/AKT/mTOR pathway Cell Proliferation Mutation TOR Serine-Threonine Kinases Tumor Suppressor Proteins Cancer Cell Biology HCT116 Cells medicine.disease In vitro Mice Inbred C57BL 030104 developmental biology 030220 oncology & carcinogenesis Cancer research Colorectal Neoplasms Ubiquitin Thiolesterase Gene Deletion |
| Zdroj: | Cell Death Differ |
| ISSN: | 1476-5403 1350-9047 |
| DOI: | 10.1038/s41418-019-0420-8 |
| Popis: | USP22, the deubiquitinating subunit of the SAGA transcriptional cofactor complex, is a member of an 11-gene "death-from-cancer" signature. USP22 has been considered an attractive therapeutic target since high levels of its expression were associated with distant metastasis, poor survival, and high recurrence rates in a wide variety of solid tumors, including colorectal cancer (CRC). We sought to investigate the role of Usp22 during tumorigenesis in vivo using a mouse model for intestinal carcinogenesis with a tissue-specific Usp22 ablation. In addition, we assessed the effects of USP22 depletion in human CRC cells on tumorigenic potential and identified underlying molecular mechanisms. For the first time, we report that USP22 has an unexpected tumor-suppressive function in vivo. Intriguingly, intestine-specific Usp22 deletion exacerbated the tumor phenotype caused by Apc mutation, resulting in significantly decreased survival and higher intestinal tumor incidence. Accordingly, human CRC cells showed increased tumorigenic properties upon USP22 reduction in vitro and in vivo and induced gene expression signatures associated with an unfavorable outcome in CRC patients. Notably, USP22 loss resulted in increased mTOR activity with the tumorigenic properties elicited by the loss of USP22 being reversible by mTOR inhibitor treatment in vitro and in vivo. Here, we demonstrate that USP22 can exert tumor-suppressive functions in CRC where its loss increases CRC burden by modulating mTOR activity. Importantly, our data uncover a tumor- and context-specific role of USP22, suggesting that USP22 expression could serve as a marker for therapeutic stratification of cancer patients. |
| Databáze: | OpenAIRE |
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