College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
Tianjin Institute of Obstetrics and Gynecology, Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China.
Cell Biol Toxicol. 2024 Apr 17;40(1):23. doi: 10.1007/s10565-024-09862-9.
Cytosolic 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.
细胞质硫脲酶 2（CTU2）是一种在后转录水平修饰转移 RNA 的酶，它与乳腺癌和黑色素瘤的发展有关。在这里，我们发现 CTU2 参与了肝细胞癌（HCC）的进展。我们分别使用 HepG2 细胞和异种移植裸鼠模型在体外和体内研究了 CTU2 在 HCC 发展中的作用。此外，我们将 CTU2 定义为肝 X 受体（LXR）的靶基因，其启动子中存在典型的 LXR 元件。CTU2 的表达受 LXR 激动剂激活，受 LXR 敲除抑制。有趣的是，我们还发现 CTU2 通过直接增强脂质生成蛋白的合成参与脂质生成，为 LXR 调节脂质合成提供了一种新的机制。同时，在细胞增殖过程中，特别是在肿瘤细胞中，脂肪生成活跃。降低 CTU2 的表达与减少肿瘤负担有关，并通过诱导肿瘤细胞凋亡和抑制细胞增殖增强了 LXR 配体的抗肿瘤作用。总之，我们的研究确定 CTU2 为 LXR 的靶基因。抑制 CTU2 的表达可以增强 LXR 配体在 HCC 中的抗肿瘤作用，这表明 CTU2 是 HCC 治疗的一个有前途的靶点，并为 LXR 激动剂在抗肿瘤作用中的应用提供了一种新的策略。
