A UMBC research team found that lowering levels of the enzyme slows cancer-cell growth, causes DNA damage during division, and makes tumors more vulnerable to common chemotherapy drugs like carboplatin and paclitaxel.
How USP15 Stabilizes Mutated p53 Proteins to Drive Tumor Growth
Ovarian cancer is frequently diagnosed only after the disease has spread to other parts of the body, leaving the five-year survival rate under 30 percent. Traditional treatments often harm healthy cells alongside malignant ones, but new laboratory findings point toward a more selective approach. The research focuses on an enzyme called USP15, which ovarian cancer cells rely on more heavily than normal cells.
The discovery began serendipitously while Achuth Padmanabhan was studying the protein p53 as a postdoctoral fellow at Baylor College of Medicine. While normal p53 helps prevent tumor formation, mutations in the gene coding for it occur in nearly every case of the most common and lethal form of ovarian cancer. Rather than simply disabling the body’s natural brakes on cancer, two-thirds of these mutations convert that braking function into a stuck accelerator, enhancing progression and causing the mutant protein to linger in the cell much longer than normal.
Further investigation revealed that USP15 is responsible for stabilizing a particular p53 mutant by removing small molecular tags that normally mark proteins for degradation. With abundant USP15 present, fewer mutant proteins face destruction, allowing cancer progression to accelerate.
Experimental Results in Cells and Mice Reveal Vulnerabilities
After returning to UMBC as a faculty member in 2019, Padmanabhan established a research group to explore the broader roles of USP15. Biological sciences Ph.D. student Ayokunnumi Ogunsanya joined the lab in 2021 and led subsequent experiments testing the enzyme’s role using both cell cultures and mouse models.
Lowering USP15 levels triggered a cascade of effects that hobbled the cancer cells. The reduction slowed cell growth, prevented chromosomes from separating cleanly during division—which led directly to DNA damage and cell death—and diminished the ability of the cells to migrate and invade other tissues.
Reducing the enzyme also made the cancer cells more vulnerable to standard treatment drugs, including carboplatin, paclitaxel, and doxorubicin. Researchers noted that lower doses of these toxic therapies might achieve the same therapeutic effects if less USP15 is present.
Overcoming Experimental Hurdles and Looking Toward Drug Development
The path to these findings required persistence. Some early experimental results ran counter to expectations, requiring the team to repeat tests and approach their biological questions from multiple angles.
Padmanabhan praised the leadership of his student researcher in driving the project forward through these unexpected turns.
Ayo is able to think through a project and see different possibilities. I’ll suggest an experiment and she’ll say, ‘I’ve already done it.
Achuth Padmanabhan, Assistant Professor, Biological Sciences, via UMBC
The findings were published on September 17 in Molecular Therapy Oncology. Moving forward, the research team aims to understand what controls USP15 levels inside cancer cells and whether inhibiting the enzyme alters a tumor’s immediate surroundings. While scientists must still determine how to lower USP15 levels safely in human patients, existing molecules used to inhibit the enzyme in laboratory settings provide a starting point for future drug development.
Broader Context in Targeted Protein Degradation
The UMBC team’s work on USP15 intersects with a wider shift in oncology toward targeted protein degradation, which offers an alternative to traditional inhibitors by clearing away proteins that drive disease. While classical chemotherapy and radiotherapy often cause significant side effects like neurotoxicity, hepatotoxicity, and drug resistance, newer precision strategies aim to interact specifically with target proteins to promote their destruction.
Cellular homeostasis relies heavily on protein degradation pathways, primarily the ubiquitin-proteasome system where E3 ubiquitin ligases mark specific substrates for elimination. Researchers across biomedical sciences are actively exploring various degrader technologies, including PROteolysis Targeting Chimeras, LYsosome-Targeting Chimeras, and DeUBiquitinase-Targeting Chimeras (DUBTACs) which mediate the recruitment of deubiquitinases to prevent the destruction of specific proteins.