Activation of CTU2 expression by LXR promotes the development of hepatocellular carcinoma

Abstract

AbstractCytosolic thiouridylase 2 (CTU2) is an enzyme modifying transfer RNAs post-transcriptionally, which has been implicated in breast cancer and melanoma development. And we found CTU2 participated in hepatocellular carcinoma (HCC) progression here. HepG2 cells as well as xenograft nude mice model were employed to investigate the role of CTU2 in HCC development in vitro and in vivo respectively. Further, we defined CTU2 as a Liver X receptor (LXR) targeted gene, with a typical LXR element in the CTU2 promoter. CTU2 expression was activated by LXR agonist and depressed by LXR knockout. Interestingly, we also found CTU2 took part in lipogenesis by directly enhancing the synthesis of lipogenic proteins, which provided a novel mechanism for LXR regulating lipid synthesis. Meanwhile, lipogenesis was active during cell proliferation, particularly in tumor cells. Reduction of CTU2 expression was related to reduced tumor burden and synergized anti-tumor effect of LXR ligands by inducing tumor cell apoptosis and inhibiting cell proliferation. Taken together, our study identified CTU2 as an LXR target gene. Inhibition of CTU2 expression could enhance the anti-tumor effect of LXR ligand in HCC, identifying CTU2 as a promising target for HCC treatment and providing a novel strategy for the application of LXR agonists in anti-tumor effect. Graphical Abstract 1.) CTU2 enhances proliferation of hepatoma carcinoma cells. 2.) CTU2 is the target gene of LXR, and LXR can transcriptionally activate CTU2 expression. 3.) CTU2 can promote protein synthesis of lipogenic genes. 4.) Inhibiting CTU2 expression can synergistically enhance the inhibitory effects of LXR ligands on HCC growth.