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

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

机构地区：[1]State Key Laboratory of Medicinal Chemical Biology,Tianjin Key Laboratory of Protein Sciences,Department of Biochemistry and Molecular Biology,College of Life Sciences,Nankai University,Tianjin 300071,China [2]Chinese Academy of Medical Sciences&Peking Union Medical College Institute of Biomedical Engineering,Tianjin 300192,China [3]Institute of Radiation Medicine,Peking Union Medical College&Chinese Academy of Medical Sciences,Tianjin 300192,China [4]Center for Cell Structure and Function,Shandong Provincial Key Laboratory of Animal Resistance Biology,Collaborative Innovation Center of Cell Biology in Universities of Shandong,College of Life Sciences,Shandong Normal University,Jinan 250014,China

出　　处：《Acta Pharmacologica Sinica》2024年第12期2625-2645,共21页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82072943 and 82072929).

摘　　要：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.

关 键 词：liver cancer CHOP LAMTOR5 lenvatinib DNA methylation miR-182/miR-769 

分 类 号：R730[医药卫生—肿瘤]