Abstract
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.
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Acknowledgements
The authors are grateful to N. Molitor and S. Beuermann for their technical assistance and the staff of the animal facility at the European Neuroscience Institute Göttingen (ENI-G). Furthermore, we thank S. Becker for performing FACS at the Cell Sorting Core Facility, Department of Hematology and Medical Oncology, University Medicine Göttingen (UMG), Göttingen, as well as G. Salinas and F. Ludewig for performing next-generation sequencing at the Transcriptome and Genome Analysis Laboratory (TAL) Göttingen. This work was supported by funding from the Roggenbuck Foundation (to RLK) and institutional funding provided to the Department of General, Visceral and Pediatric Surgery by the University Medical Center Göttingen (to SAJ). RLK is supported by the Dorothea Schlözer program (University of Göttingen).
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SAJ and RLK designed the study with input from YB-N. RLK performed all the cell culture experiments with the help of MZ and DS. Next-generation sequencing data were generated and analyzed by RLK and FW provided support with bioinformatic analyses. Mouse experiments were performed by RLK with the help of FW, DS, and MZ. Histological analyses were carried out by RLK and LW. ChIP was performed by RLK and MZ with the help of XW. SAJ and RLK wrote the manuscript. All authors have read and approved the final version of the article, including the authorship list.
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Kosinsky, R.L., Zerche, M., Saul, D. et al. USP22 exerts tumor-suppressive functions in colorectal cancer by decreasing mTOR activity. Cell Death Differ 27, 1328–1340 (2020). https://doi.org/10.1038/s41418-019-0420-8
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DOI: https://doi.org/10.1038/s41418-019-0420-8
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