Endocrine Abstracts

JOINT1984

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with an incidence of one case per million people per year and a 5-year overall survival rate of less than 35%. Currently, complete surgical resection is the only curative treatment, while mitotane, an adrenolytic drug, remains the sole approved systemic therapeutic option besides platinum-based chemotherapy. Given these limitations, there is an urgent need for innovative therapeutic approaches. The ubiquitin-proteasome system (UPS) is an essential cellular machinery that regulates protein stability and is known to be hijacked by tumor cells to exploit signaling pathways and sustain highly proliferative states. However, the role of deubiquitinases (DUBs) in adrenocortical tumors remains poorly understood. Analyzing publicly available datasets, we prioritized DUBs associated with patient survival in ACC and its most relevant signaling pathways. Among these, USP10 emerged as a particularly compelling candidate in follow-up In vitro studies. Analysis of Immunohistochemical staining of USP10 on tissue microarrays (TMAs; n: number of single cores) revealed significantly higher USP10 expression in ACC (n = 645; P < 0. 001) and adrenocortical adenomas (n = 128; P < 0. 01) compared to normal adrenal gland (n = 42). Subsequential analysis of adenomas by hormonal status showed an increased USP10 expression in cortisol-producing adenomas (n = 95) compared to hormonally inactive adenomas (n = 12; P < 0. 001), which is in line with its distinct zone-specific expression we observed in the normal adrenal cortex. So far, we were able to obtain complete clinical datasets for 121 ACC specimens, allowing correlations between USP10 expression and clinical outcomes, including survival, chemotherapy response, hormonal status, and pathological tumor markers. Interestingly, subgroup analysis for hormonal activity showed no significant difference in USP10 expression in ACC. However, treatment with an USP10-specific inhibitor resulted in a significant reduction in cell proliferation in ACC cell lines. Combining USP10 inhibition with cisplatin elicited a synergistic anti-tumor effect, likely through interference with DNA damage response. Therefore, our preliminary analyses indicate that USP10 dysregulation in ACC might be linked to its malignant phenotype rather than hormonal activity. Subsequent In vitro experiments using LC-MS-based steroid profiling and immunoblotting of steroid biosynthesis enzymes in ACC cell lines following USP10 inhibition provided further insight into USP10’s influence on hormone production. In conclusion, our findings show evidence for USP10 dysregulation in adrenocortical tumors. Its multifaceted role in tumor biology, including DNA damage response and steroidogenesis, suggests a complex contribution to tumorigenesis, with potential clinical implications for diagnosis and treatment.