Ubiquitin-independent pathway regulates the RIT1-MAPK pathway in chordoma progression.

Chordoma is a rare, slow-growing malignant tumor originating from embryonic notochord remnants and is often found in the sacrum or skull base. It is categorized into conventional, poorly differentiated, and dedifferentiated types, with the conventional type being the most common. Owing to its location near critical structures, chordoma has a high rate of local recurrence, making new therapeutic targets essential. The proteasome system, which is responsible for degrading intracellular proteins, plays a vital role in maintaining cellular function. REGγ, a proteasome activator, mediates ubiquitin-, and ATP-independent protein degradation and is overexpressed in various cancers. However, its role in chordoma remains unexplored. Ras GTPases, including RIT1, are involved in cancer progression, and understanding their involvement in chordoma could provide therapeutic insights. This study identified REGγ as a potential therapeutic target for chordoma. REGγ was found to be upregulated in chordoma, and high REGγ expression was correlated with poor clinical outcomes. It promotes cell proliferation and migration, and inhibits apoptosis, while influencing osteoclast differentiation. Mechanistically, REGγ regulates chordoma progression through the ubiquitin- and ATP-independent degradation of RIT1, which modulates the RIT1-MAPK pathway. Inhibition of RIT1 in REGγ-knockdown cells and patient-derived organoids alleviated these effects, suggesting that targeting REGγ may be a promising strategy for chordoma treatment.