MTFR2 accelerates hepatocellular carcinoma mediated by metabolic reprogramming via the Akt signaling pathway

Abstract

Metabolic reprogramming has recently been identified as a hallmark of malignancies. The shift from oxidative phosphorylation to glycolysis in hepatocellular carcinoma (HCC) meets the demands of rapid cell growth and provides a microenvironment for tumor progression. This study sought to uncover the function and mechanism of MTFR2 in the metabolic reprogramming of HCC. Elevated MTFR2 expression was associated with poor patient prognosis. Downregulation of MTFR2 blocked malignant behaviors, epithelial-to-mesenchymal transition (EMT), and glycolysis in HCC cells. Nuclear transcription factor Y subunit gamma (NFYC) was also associated with poor patient prognosis, and NFYC bound to the promoter of MTFR2 to activate transcription and promote Akt signaling. The repressive effects of NFYC knockdown on EMT and glycolysis in HCC cells were compromised by MTFR2 overexpression, elicited through the activation of the Akt signaling. Knockdown of NFYC slowed the growth and intrahepatic metastasis in vivo, which was reversed by MTFR2 overexpression. In conclusion, our work shows that activation of MTFR2 by the transcription factor NFYC promotes Akt signaling, thereby potentiating metabolic reprogramming in HCC development. Targeting the NFYC/MTFR2/Akt axis may represent a therapeutic strategy for HCC.