Sirtuin 4 Depletion Promotes Hepatocellular Carcinoma Tumorigenesis Through Regulating Adenosine‐Monophosphate–Activated Protein Kinase Alpha/Mammalian Target of Rapamycin Axis in Mice

Abstract

Sirtuin 4 (SIRT4) has been reported to play a vital role in the maintenance of glutamine catabolism and adenosine triphosphate (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 knockout (KO) mice by promoting colony formation and migration of hepatoma cells and enhancing sphere formation of HCCs. Mechanistically, SIRT4 deletion augmented mammalian target of rapamycin (mTOR) signaling by inactivating adenosine‐monophosphate (AMP)‐activated protein kinase alpha (AMPKα) through regulation of glutamine catabolism and subsequent AM)/liver kinase B1 (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 hyperproliferative phenotype caused by SIRT4 loss, which further confirmed that the 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 adenosine diphosphate (ADP)/AMP levels to phosphorylate AMPKα by LKB1, which blocks the mTOR signaling pathway.

Loss of SIRT4 promotes the self-renewal of Breast Cancer Stem Cells

“…PBabe.puro retroviral construct containing human SIRT4 cDNA and pSuper.retro.puro with human SIRT4 shRNA was prepared as previously described 15 . The generation of retrovirus supernatants and the transfection of breast cancer cells were carried out.…”

The Roles of Sirtuin Family Proteins in Cancer Progression

“…SIRT4 inhibits NSCLC cell invasion and migration, perhaps affecting the invasive capability of cancer by hampering MEK/ERK activity [57]. A deficiency in SIRT4 facilitates liver tumor development and lung metastasis in mice with xenografts and Sirt4 knockout (Sirt4 -/-) by promoting colony formation and migration and enhancing the sphere formation of hepatocellular cancer cells [61]. In colorectal cancer cells, SIRT4 suppresses migration and invasion while upregulating E-cadherin expression.…”

Functions of mammalian SIRT4 in cellular metabolism and research progress in human cancer (Review)

“…The mutual inhibition between SIRT4 and mTORC1 was important for the proliferation and survival of colon carcinoma cell line DLD1 and prostate cancer cell line DU145 ( 100 , 101 ). In hepatocellular carcinomas, SIRT4 deletion by shRNA of HL7702 cell line increased mTOR signaling by inhibiting AMPK through the regulation of glutamine catabolism and the AMP/LKB1 pathway ( 80 ). In non-small cell lung cancer cell lines, SIRT4 reduced mitochondrial fission by interacting with the Fis-1/Drp1 axis and regulated cell invasive abilities by repressing MEK/ERK activity ( 81 ).…”