ECE2023 Poster Presentations Late-Breaking (40 abstracts)
Investigating the role of deubiquitinases in adrenocortical carcinoma
Victoria Louise Marnet 1,2 , Oliver Hartmann 1 , Michaela Reissland 1 , Nikolett Pahor 1 , Laura-Sophie Landwehr 2 , Martin Fassnacht 2 , Carmina Teresa Fuss 1,2 & Markus Elmar Diefenbacher 1
1University of Wuerzburg, Protein Stability and Cancer Group, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany; 2University of Wuerzburg, Division of Endocrinology and Diabetes, University Hospital, Wuerzburg, Germany
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy presenting with an incidence of 1 per million per year and an overall 5-year survival rate under 35%. Currently, curative treatment is limited to full surgical resection, while the adrenolytic drug mitotane remains the only approved medical therapy option leaving a huge demand for innovative therapeutic strategies. Genetic alterations observed in ACC commonly lead to activation of Wnt/β-Catenin signaling most frequently caused by mutations in the CTNNB1 gene encoding for the nuclear effector β-Catenin. The key players of Wnt/β-Catenin signaling are known to be under tight control of the ubiquitin-proteasome-system. However, the role of deubiquitinases (DUBs) regarding β-Catenin regulation in ACC remains unknown. Analyzing publicly available data we preselected potentially relevant DUBs linked to patient survival in ACC and Wnt-Signaling. To confirm interesting targets, we performed quantitative PCR in six established ACC cell lines leading us to further investigation of USP10. We observed elevated protein abundance in primary tumor tissue compared to the normal adrenal gland as well as a high portion of USP10 in its active state across all ACC cell lines. Continuing the characterization of USP10 expression and localization, we performed immunohistochemical stainings on Tissue Micro Arrays (TMAs). Subsequential quantification of the TMAs incorporating a manually trained algorithm to distinguish tumor and surrounding tissue confirmed significantly higher USP10 expression in ACC as well as endocrine inactive adenoma compared to normal adrenal gland. Treatment with a Pan-DUB inhibitor, the proteasome inhibitor Bortezomib and a USP10-specific inhibitor led to a reduction of cell growth in ACC cell lines. In summary, we so far found strong indication for dysregulation of USP10 in adrenocortical tumors, therefore making it potential therapeutic target in ACC.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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