南开大学叶丽虹等研究人员合作发现，肿瘤蛋白LAMTOR5通过DNA高甲基化和miR-182/miR-769介导CHOP沉默来促进肝癌生长。该研究于2024年6月28日在线发表于国际一流学术期刊《中国药理学报》。

C/EBP同源蛋白（CHOP）通过内质网（ER）应激引发多种癌症的死亡。然而，CHOP在肝癌中的功能和调控机制仍然难以捉摸。研究人员曾报道，晚期内吞体/溶酶体适配蛋白、丝裂原活化蛋白激酶和mTOR激活剂5（LAMTOR5），可抑制多种癌症的细胞凋亡。

研究人员发现LAMTOR5介导的CHOP转录和转录后失活加速了肝癌的生长。临床生物信息分析表明，CHOP在肝癌组织中的表达量较低，而其表达量的增加预示着良好的预后。CHOP的升高会破坏LAMTOR5诱导的凋亡抑制和增殖。

从机理上讲，LAMTOR5将DNA甲基转移酶1（DNMT1）招募到CHOP启动子的CpG3区（-559/-429），并增强其超甲基化，从而阻断其与通用转录因子IIi（TFII-I）的相互作用，导致其失活。此外，LAMTOR5增强的miR-182/miR-769通过靶向3'UTR降低了CHOP的表达。

值得注意的是，作为肝癌一线靶向疗法的来伐替尼可以靶向LAMTOR5/CHOP轴，防止肝癌进展。因此，LAMTOR5通过调节ER应激相关凋亡介导的CHOP沉默会促进肝癌的生长，这为来伐替尼治疗肝癌提供了理论依据。

附：英文原文

Title: Oncoprotein LAMTOR5-mediated CHOP silence via DNA hypermethylation and miR-182/miR-769 in promotion of liver cancer growth

Author: Wang, Xue, Li, Qian-qian, Tang, Yan-xin, Li, Ye, Zhang, Lu, Xu, Fei-fei, Fu, Xue-li, Ye, Kai, Ma, Jia-qi, Guo, Shi-man, Ma, Fang-yuan, Liu, Zhi-yu, Shi, Xu-he, Li, Xian-meng, Sun, Hui-min, Wu, Yue, Zhang, Wei-ying, Ye, Li-hong

Issue&Volume: 2024-06-28

Abstract: C/EBP homologous protein (CHOP) triggers the death of multiple cancers via endoplasmic reticulum (ER) stress. However, the function and regulatory mechanism of CHOP in liver cancer remain elusive. We have reported that late endosomal/lysosomal adapter, mitogen-activated protein kinase and mTOR activator 5 (LAMTOR5) suppresses apoptosis in various cancers. Here, we show that the transcriptional and posttranscriptional inactivation of CHOP mediated by LAMTOR5 accelerates liver cancer growth. Clinical bioinformatic analysis revealed that the expression of CHOP was low in liver cancer tissues and that its increased expression predicted a good prognosis. Elevated CHOP contributed to destruction of LAMTOR5-induced apoptotic suppression and proliferation. Mechanistically, LAMTOR5-recruited DNA methyltransferase 1 (DNMT1) to the CpG3 region (559/429) of the CHOP promoter and potentiated its hypermethylation to block its interaction with general transcription factor IIi (TFII-I), resulting in its inactivation. Moreover, LAMTOR5-enhanced miR-182/miR-769 reduced CHOP expression by targeting its 3’UTR. Notably, lenvatinib, a first-line targeted therapy for liver cancer, could target the LAMTOR5/CHOP axis to prevent liver cancer progression. Accordingly, LAMTOR5-mediated silencing of CHOP via the regulation of ER stress-related apoptosis promotes liver cancer growth, providing a theoretical basis for the use of lenvatinib for the treatment of liver cancer.

DOI: 10.1038/s41401-024-01310-y

Source: https://www.nature.com/articles/s41401-024-01310-y