Overexpression of SLC25A51 promotes hepatocellular carcinoma progression by driving aerobic glycolysis through activation of SIRT5

Solute carrier family 25 member 20 (SLC25A51) is a newly identified mammalian mitochondrial NAD+ transporter. However, the clinicopathological and biological significance of SLC25A51 in human cancers, including hepatocellular carcinoma (HCC), remains unclear. The aim of this study was to define the role of SLC25A51 in HCC progression. Here we demonstrate that SLC25A51 is significantly overexpressed in human HCC specimens and cell lines, caused by, at least in partial, the decrease of miR-212-3p. SLC25A51 overexpression is positively correlated with the clinicopathological characteristics of vascular invasion and tumor diameter, as well as poor survival in patients with HCC. Knockdown of SLC25A51 attenuated, while overexpression of SLC25A51 enhanced the growth and metastasis of HCC cells both in vitro and in vivo. Mechanistically, glucose metabolism reprogramming from oxidative phosphorylation to glycolysis by activation of mitochondrial sirtuin 5 (SIRT5) was found to contribute to the promotion of growth and metastasis by SLC25A51 in HCC cells. Together, these findings reveal important roles of SLC25A51 in HCC tumorigenesis and suggest SLC25A51 as a promising prognostic marker and therapeutic target for treating HCC.