USP15 regulates mitotic fidelity, metastatic potential, and chemotherapeutic response in ovarian cancer cells.

Aggressive metastasis and chemoresistance are underlying cause for the poor clinical outcome in ovarian cancer patients. Identifying factors that drive these phenotypes is critical in developing effective therapeutic strategies for metastatic ovarian cancer. In this report, we show that the deubiquitinase USP15 is a critical regulator of ovarian cancer cell proliferation, metastasis, and drug resistance. USP15 levels are elevated in metastatic ovarian tumors and are associated with poor clinical outcome in patients. Depletion and inhibition of USP15 dramatically reduces cell viability and proliferation in a broad spectrum of ovarian cancer cells. Mechanistically, USP15 knockdown disrupts chromosomal segregation, leading to DNA damage, micronuclei formation, and mitotic catastrophe. This causes ovarian cancer cells to undergo cell-cycle arrest at the G2-M checkpoint. Further, USP15 knockdown decreases the metastatic potential of ovarian cancer cells in vitro, reduces tumor burden, and extends survival in mouse xenograft models. Consistent with its role in maintaining mitotic fidelity, USP15 depletion sensitizes ovarian cancer cells to mitotic inhibitors and DNA damage inducing chemotherapeutics. Collectively, these findings establish USP15 as a key driver of ovarian cancer metastasis and highlight its potential as an actionable therapeutic target to improve the effectiveness of extant chemotherapeutic agents.