SIRT4 Protein Suppresses Tumor Formation in Genetic Models of Myc-induced B Cell Lymphoma

Background: Glutamine metabolism is essential for Myc-induced tumors. Results: SIRT4 regulates mitochondrial glutamine metabolism and the growth and survival of Burkitt lymphoma cells independent of Myc. Conclusion: SIRT4 has a tumor-suppressive role in Myc-induced B cell lymphoma. Significance: SIRT4 may be a potential target against Myc-driven and glutamine-dependent tumors. Glutamine metabolism plays an essential role for growth and proliferation of many cancer cells by providing metabolites for the maintenance of mitochondrial functions and macromolecular synthesis. Aberrant activation of the transcription factor c-Myc, e.g. caused by t(8;14) chromosomal translocation commonly found in Burkitt lymphoma, is a key driver of cellular glutamine metabolism in many tumors, highlighting the need to identify molecular mechanisms that can suppress glutamine usage in these cancers. Recently, the mitochondrial sirtuin SIRT4 has been reported to function as a tumor suppressor by regulating glutamine metabolism, suggesting that it might have therapeutic potential for treating glutamine-dependent cancers. Here, we report that SIRT4 represses Myc-induced B cell lymphomagenesis via inhibition of mitochondrial glutamine metabolism. We found that SIRT4 overexpression can dampen glutamine utilization even in Myc-driven human Burkitt lymphoma cells and inhibit glutamine-dependent proliferation of these cells. Importantly, SIRT4 overexpression sensitizes Burkitt lymphoma cells to glucose depletion and synergizes with pharmacological glycolysis inhibitors to induce cell death. Moreover, SIRT4 loss in a genetic mouse model of Myc-induced Burkitt lymphoma, E-Myc transgenic mouse, greatly accelerates lymphomagenesis and mortality. Indeed, E-Myc-induced B cell lymphoma cells from SIRT4 null mice exhibit increased glutamine uptake and glutamate dehydrogenase activity. Furthermore, we establish that SIRT4 regulates glutamine metabolism independent of Myc. Together, these results highlight the tumor-suppressive role of SIRT4 in Myc-induced B cell lymphoma and suggest that SIRT4 may be a potential target against Myc-induced and/or glutamine-dependent cancers.