SEMA5B depletion suppresses cell proliferation and glycolysis by downregulating VDAC2 expression in esophageal...

Although Semaphorin 5B (SEMA5B) has been reported to be involved in tumor progression, the underlying mechanisms in esophageal squamous cell carcinoma (ESCC) are still largely unknown. In this study, we found that SEMA5B gene was significantly upregulated in both ESCC samples and cell lines. Knockdown of SEMA5B suppressed cell proliferation, migration, and invasion in ESCC cells, whereas its overexpression produced the opposite effects. Notably, SEMA5B depletion markedly reduced glucose consumption and lactate production, and downregulated the expressions of key glycolytic enzymes, including hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), phosphofructokinase, muscle-type (PFKM), and lactate dehydrogenase A (LDHA). Conversely, SEMA5B overexpression enhanced glycolytic activity. Mechanistically, SEMA5B interacted with voltage-dependent anion channel 2 (VDAC2) in ESCC cells and stabilized VDAC2 protein by suppressing the expression of the E3 ubiquitin ligase neural precursor cell expressed, developmentally down-regulated protein 4 (NEDD4). VDAC2 was overexpressed in ESCC samples compared to normal controls, and its knockdown dramatically inhibited the expressions of glycolytic proteins. Importantly, the pro-glycolytic effect of SEMA5B was attenuated by VDAC2 silencing, while VDAC2 overexpression partially rescued the glycolytic suppression caused by SEMA5B knockdown.. In conclusion, our current data suggest that SEMA5B promotes glycolysis by upregulating VDAC2 in ESCC cells, and thus targeting SEMA5B-VDAC2 signal axis may be a novel therapeutic strategy for ESCC patients.