Abstract Ovarian cancer remains one of the deadliest gynecologic malignancies and the sixth leading cause of cancer-related death among women in the United States. Poor clinical outcomes are largely driven by late diagnosis and limited therapeutic options for metastatic disease. Therefore, there is an urgent need to identify molecular drivers of ovarian cancer progression and develop strategies to target them. Analysis of tumor gene expression datasets revealed that the deubiquitinase USP15 is significantly upregulated in metastatic ovarian tumors compared to normal tissues. Elevated USP15 expression also correlates with decreased progression-free survival in patients. Although USP15 has been shown to promote tumorigenesis in several cancer types, its role and the mechanisms regulating its levels in ovarian cancer remain poorly understood.We hypothesize that elevated USP15 promotes ovarian cancer progression and metastasis, and that its depletion sensitizes tumors to chemotherapeutic agents. To test this, we generated stable USP15 knockdown ovarian cancer cell lines and assessed metastatic properties using in vitro assays and in vivo xenograft models. Mechanistic studies examined cell-cycle and DNA damage responses via flow cytometry and western blotting.USP15 knockdown significantly reduced cell proliferation, migration, and invasion of ovarian cancer cells. In xenograft models, USP15 depletion suppressed metastasis, confirming its role in promoting ovarian tumor progression. Cell-cycle analysis revealed a G2/M arrest phenotype in USP15-depleted cells, consistent with impaired cell-cycle progression or checkpoint activation. Western blotting also showed altered expression of key cell-cycle regulators and increased activation of DNA damage markers.Collectively, these findings indicate that USP15 regulates ovarian cancer cell-cycle progression, checkpoint control, and DNA damage responses. Targeting USP15 may therefore represent a promising strategy to inhibit ovarian tumor progression and metastasis. Citation Format: Ayokunnumi Sewanu Ogunsanya, Noel Amadu, Achuth Padmanabhan. USP15 promotes ovarian cancer progression by modulating cell cycle checkpoints and DNA damage signaling abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6088.
Ogunsanya et al. (Fri,) studied this question.