SIRT4 Depletion Promotes HCC Tumorigenesis through Regulating AMPKα/mTOR Axis

Abstract

Sirtuin 4 (SIRT4) has been reported to play a vital role in the maintenance of glutamine catabolism and ATP homeostasis, but its character in hepatocellular carcinomas (HCCs) remains obscure. In this study, we observed low expression of SIRT4 in both HCC cell lines and HCCs from patients. Decreased disease‐free survival time is associated with low tumor levels of SIRT4 in patients. Deficiency of SIRT4 facilitated liver tumor development and lung metastasis in xenografts and KO mice by promoting the colony formation and migration of hepatoma cells and enhancing the sphere formation of HCCs. Mechanistically, SIRT4 deletion augmented mammalian target of rapamycin (mTOR) signaling by inactivating AMPKα through regulation of glutamine catabolism and subsequent AMP/LKB1 axis. Blockage of mTOR by rapamycin or inhibition of glutaminolysis abolished the discrepancy in tumorigenic capacity between SIRT4‐depleted hepatoma cells and control cells. Suppression of LKB1 or promotion of AMP by metformin also abrogated the hyper‐proliferative phenotype caused by SIRT4 loss, which further confirmed that LKB1/AMPKα/mTOR axis is required in SIRT4‐deficiency‐promoted HCC tumorigenesis. Conclusion SIRT4 could exert its tumor suppressive function in HCC by inhibiting glutamine metabolism and thereby increasing the ADP/AMP levels to phosphorylate AMPKα via LKB1, which blocks mTOR signaling pathway.

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