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The tumor suppressor role of mitochondrial E3 ubiquitin ligase MUL1 in osteosarcoma
Jacopo Di Gregorio1, Sara Terreri2, Michela Rossi3
1Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
Abstract:
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.
Insights
Mitochondrial E3 ubiquitin ligase MUL1 acts as a tumor suppressor in osteosarcoma. Increasing MUL1 levels degrades hypoxia-inducible factor HIF-1α, reducing cancer cell proliferation and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Osteosarcoma is an aggressive bone cancer with poorly understood metastatic mechanisms.
- Hypoxia-inducible factor 1-alpha (HIF-1α) is upregulated in metastatic osteosarcoma, promoting cancer progression.
- Mitochondrial E3 ubiquitin ligase MUL1 influences HIF-1α stability, presenting a potential therapeutic target.
Purpose of the Study:
- To investigate the role of MUL1 in osteosarcoma metastasis.
- To determine the relationship between MUL1 protein levels and osteosarcoma aggressiveness.
- To explore the therapeutic potential of modulating MUL1 for osteosarcoma treatment.
Main Methods:
- Correlation analysis of MUL1 protein levels with osteosarcoma cell line aggressiveness.
- Experimental manipulation of MUL1 levels in osteosarcoma cells (induction and inactivation).
- Assessment of HIF-1α levels, cell proliferation, migration, apoptosis, and glycolysis.
Main Results:
- MUL1 protein levels inversely correlate with osteosarcoma aggressiveness.
- Induction of MUL1 in aggressive cells decreased HIF-1α, proliferation, migration, and glycolysis, while increasing apoptosis.
- Inactivation of MUL1 in less aggressive cells yielded opposite effects.
Conclusions:
- MUL1 functions as a tumor suppressor in osteosarcoma.
- Modulating MUL1 levels impacts key cancer hallmarks including proliferation, migration, apoptosis, and metabolism.
- MUL1 induction represents a potential therapeutic strategy to inhibit HIF-1α activity and combat osteosarcoma metastasis.
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