TRIM17 promotes the progression of osteosarcoma by regulating PDK1 m6A modification-mediated AKT/mTOR pathway activation through ubiquitination of FTO

Osteosarcoma is an extremely aggressive malignant tumor, which is quite common among children and has a high rate of disability and mortality. Tripartite Motif Containing 17 (TRIM17) is a member of the TRIM protein family and exhibits E3 ubiquitin ligase activity. In recent years, TRIM17 has been implicated in the development of various tumors, particularly in cancer cell clonability and survival potential and drug resistance; however, its regulatory mechanism in osteosarcoma progression remains poorly understood. We found that TRIM17 was significantly upregulated in osteosarcoma tissues and cells. Survival analysis revealed that TRIM17 was associated with poor prognosis in osteosarcoma patients. The higher the expression level of TRIM17, the worse the prognosis. Its expression was an independent prognostic factor for osteosarcoma patients. The effects of TRIM17 on osteosarcoma cell clonability and survival potential, migration, and invasion were assessed through phenotypic assays. The results showed that the downregulation of TRIM17 significantly inhibited osteosarcoma cell clonability and survival potential, migration, and invasion, whereas its overexpression promoted these processes. FTO is an m6A methyltransferase and has been identified as a new target for TRIM17. Mechanistically, TRIM17 promotes the ubiquitination and degradation of FTO protein, enhances PDK1 mRNA stability via N6-methyladenosine (m6A) modification, and subsequently promotes phosphorylation-dependent activation of the AKT/mTOR signaling pathway, thereby driving osteosarcoma malignancy. In summary, our findings suggest that TRIM17 may serve as a potential prognostic marker and therapeutic target for osteosarcoma.