BCAT1 as a critical regulator of human chondrosarcoma progression and differentiation through enzymatic and non-enzymatic mechanisms

Human chondrosarcoma is a malignant bone tumor with a poor prognosis due to its resistance to conventional therapies. In this study, we investigated the role of Branched-Chain Amino Acid Transaminase 1 (BCAT1) in chondrosarcoma pathogenesis. BCAT1 depletion impairs proliferation and tumorigenicity both in vitro and in vivo in a xenograft model, underscoring its oncogenic role. Transcriptome analyses revealed that BCAT1 suppresses the chondrocyte differentiation pathway by inhibiting the expression of SOX9, a master regulator of normal chondrogenesis, through epigenetic regulation. This process depends on BCAT1’s enzymatic activity to generate α-ketoglutarate, which subsequently alters histone methylation status. Additionally, the CXXC motif of BCAT1 scavenges reactive oxygen species (ROS) independently of its enzymatic activity, maintaining G2/M checkpoint signaling and preventing ROS-induced cellular senescence. Finally, knockdown experiments in patient-derived primary cells confirm the clinical significance of BCAT1 function in human chondrosarcoma. These findings establish BCAT1 as a critical moonlighting enzyme in chondrosarcoma proliferation and differentiation, presenting a potential therapeutic target for this challenging cancer.