Abstract B025: Determining the role and regulation of USP15 in ovarian cancer metastasis

Ovarian cancer is the second most lethal gynecologic cancer and the sixth cause of cancer-related deaths among women in the United States. Two major factors that contribute to this clinical reality are our inability to diagnose ovarian cancer early and the ineffectiveness of current therapeutics to treat metastatic ovarian cancer. Therefore, there is an urgent need to identify cellular factors that promote ovarian cancer metastasis and develop strategies to target them. Analysis of tumor gene expression datasets reveals that the levels of a deubiquitinase enzyme USP15, are elevated in metastatic ovarian tumors compared to normal tissues. Interestingly, high USP15 levels in ovarian tumors correlate with decreased progression-free survival in patients. Although USP15 is known to promote tumorigenesis in several cancers, its precise role in ovarian cancer and the mechanisms that regulate USP15 levels in cells remains unknown. We hypothesize that elevated USP15 promotes ovarian cancer progression and metastasis, and its depletion will sensitize ovarian tumors to chemotherapeutic agents. To test this, we generated stable USP15 knockdown cell lines using lentiviral gene-mediated delivery. We then performed various in-vitro assays to determine the effect of USP15 knockdown on proliferation, migration, and invasion. We show that USP15 knockdown in ovarian cancer cells decreases cell proliferation, migration, and invasive potential of these cells in vitro. Further, we also discovered that a small molecule called MCB613, a steroid receptor co-activator, decreases USP15 stability and levels via a post-translational mechanism. Future work will determine the mechanisms by which USP15 promotes ovarian cancer progression. We will also use MCB-613 as a tool to identify pathways that regulate USP15 stability in cells. Citation Format: Ayokunnumi Sewanu. Ogunsanya, Achuth Padmanabhan. Determining the role and regulation of USP15 in ovarian cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B025.