The tumor suppressor role of mitochondrial E3 ubiquitin ligase MUL1 in osteosarcoma

Osteosarcoma is a highly aggressive type of bone cancer with a high rate of metastasis. The molecular mechanisms underlying osteosarcoma metastasis are not yet completely understood, representing an ongoing challenge for therapy. A possible therapeutic target is the hypoxia-inducible factor HIF-1α which is upregulated in metastatic osteosarcoma. Indeed, HIF-1α promotes proliferation, resistance to apoptosis and metabolic reprogramming towards glycolysis, whereas its downregulation increases apoptosis. The molecular mechanism mediated by the mitochondrial E3 ubiquitin ligase MUL1 could be exploited to target HIF-1α since low MUL1 protein levels result in HIF-1α accumulation and activity even under normoxic conditions, while high levels of MUL1 promote HIF-1α degradation. Here, we show that MUL1 protein levels inversely correlate with the aggressiveness of osteosarcoma cell lines. Induction of MUL1 in aggressive cells reduces HIF-1α levels, paired with a decrease in proliferation, migration and glycolysis and increase in apoptosis, whereas MUL1 inactivation in low-aggressive cells has opposite results. Therefore, the modulation of MUL1 protein levels affects cell proliferation, migration, apoptosis, and metabolism. This is the first report that reveals a tumor suppressor role for MUL1 in osteosarcoma, and suggests MUL1 induction as a potential therapeutic strategy to reduce HIF-1α activity in the metastatic progression of this cancer.