ZNF217-USP15 signaling loop regulates oncogenic phenotypes in ovarian cancer cells

A recent study has uncovered a crucial mechanism behind the aggressive behavior of ovarian cancer cells, particularly those driven by the oncogenic transcription factor ZNF217. Researchers identified ubiquitin-specific peptidase 15 (USP15) as a key player in controlling ZNF217 stability, establishing a reciprocal signaling loop that sustains malignant traits in ovarian cancer.

When ZNF217 levels were artificially boosted in ovarian cancer cells, the protein's abundance surged, boosting its capacity for proliferation, epithelial-mesenchymal transition, migration, invasion, and extracellular matrix adhesion. Intriguingly, this increase in ZNF217 did not alter its mRNA levels, indicating a post-transcriptional regulation. On the flip side, reducing ZNF217 levels led to a drop in USP15 protein, suggesting USP15's regulation of ZNF217 primarily occurs at the post-transcriptional level.

Moreover, inhibiting the proteasome, a cellular machinery that degrades proteins, restored ZNF217 levels post USP15 depletion, further emphasizing USP15's role in stabilizing ZNF217 protein. Functionally, decreasing USP15 levels in ZNF217-overexpressing ovarian cancer cells curbed proliferation and several metastatic features such as migration, invasion, extracellular matrix adhesion, resistance to anoikis, and formation of multicellular aggregates.

In animal models bearing ZNF217-driven ovarian tumors, USP15 depletion reduced tumor progression, metastasis, and prolonged survival.

Additionally, USP15 depletion made cells expressing ZNF217 more sensitive to chemotherapy drugs like carboplatin, paclitaxel, and doxorubicin. These findings collectively unveil USP15 as an upstream regulator of ZNF217 protein stability, presenting a promising indirect therapeutic approach for suppressing ZNF217-driven ovarian cancer.