Tripartite Motif-Containing 46 Promotes Viability and Inhibits Apoptosis of Osteosarcoma Cells by Activating NF-kB Signaling through Ubiquitination of PPARa

Abstract

Osteosarcoma (OS), the most common bone cancer, causes high morbidity in children and young adults. TRIM46 is a member of the family of tripartite motif (TRIM)-containing proteins that serve as important regulators of tumorigenesis. Here we investigate the possible role of TRIM46 in OS and the underlying molecular mechanism. We report an increase in the expression of TRIM46 in OS and its association with tumor size, Enneking’s stage, and patient prognosis. TRIM46 knockdown inhibits OS cell viability and cell cycle progression and induces apoptosis, while TRIM46 overexpression exerts inverse effects, which are inhibited by peroxisome proliferator-activated receptor alpha (PPARa) overexpression and the nuclear factor kappa B (NF-kB) inhibitor, pyrrolidine dithiocarbamate (PDTC). Furthermore, TRIM46 negatively regulates PPARa expression via ubiquitination-mediated protein degradation and modification. PPARa overexpression also inactivates NF-kB signaling and NF-kB promoter activity in OS cells overexpressing TRIM46. Moreover, TRIM46 knockdown inhibits tumor growth and induces apoptosis of OS cells in vivo. TRIM46 acts as an oncogene in OS by interacting with and ubiquitinating PPARa, resulting in the activation of NF-kB signaling pathway. Thus, TRIM46 may be a potential biomarker of carcinogenesis.