SUN2 exerts tumor suppressor functions by suppressing the Warburg effect in lung cancer

Lung cancer is the leading cause of cancer-related mortality worldwide1,2,3, being associated with an overall 5-year survival rate lower than 16%4,5,6.The dysregulation of oncogenes or tumor suppressor genes is tightly correlated with the initiation, progression and resistance to therapy of lung cancer7,8,9, all of which involve changes in the biological characteristics of cancer cells, including cell growth, apoptosis, migration, invasion, and metabolism. However, the molecular mechanisms of lung cancer pathogenesis are still poorly understood. Therefore, the identification of novel therapeutic targets, to develop less toxic therapies, as well as better predictive markers is urgently needed. SUN2, a Sad1 and UNC84 domain protein, is located at the inner nuclear membrane, extending into the perinuclear space via its C-terminal SUN domain and interacting with the nuclear lamina through its nucleoplasmic N-terminal domain10,11,12. SUN2 is a member of the inner nuclear membrane LINC (linker of nucleoskeleton and cytoskeleton) complex, which maintains nuclear structure by connecting the nuclear lamina to the cytoskeleton10. Dysregulation of the LINC complex is associated with many human diseases, including cancers10,11,13. Hsieh TH et al. demonstrated, for the first time, that SUN2 plays a tumor suppressor role in miR-221/22-mediated malignant central nervous system embryonal tumors, in which SUN2 inhibits cell proliferation and tumor malignancy both in vitro and in vivo14. The mRNA and protein levels of SUN2 are decreased in breast tumor tissues compared with mammary epithelial tissues15. However, the role of SUN2 in lung cancer remains uncharacterized, and the mechanism by which SUN2 regulates cancer cell biological characteristics also needs to be addressed. The majority of cancer cells exhibit elevated glucose uptake and lactate production, regardless of oxygen availability16,17, which has long been known as aerobic glycolysis, or the Warburg effect. The Warburg effect promotes cancer cell growth and evasion of apoptosis and can be targeted for cancer therapy18. It has recently been reported that loss of tumor suppressors or activation of oncogenes is involved in the Warburg effect. For example, the oncogenes AKT, c-Myc, and Ras promote the Warburg effect, whereas the tumor suppressors p53 and PTEN inhibit the Warburg effect in cancer cells17,18,19. However, the molecular mechanism underlying the Warburg effect in cancer cells is not fully understood. In this study, we provide the first evidence that SUN2 plays a tumor suppressor role by suppressing the expression of GLUT1 and LDHA to inhibit the Warburg effect in lung cancer. We also show that the down-regulation of SUN2 is at least partly mediated by class III of the sirtuin family member SIRT5 in lung cancer. This novel SIRT5/SUN2 axis may be valuable for developing new strategies for treating patients with lung cancer.