Cargando…

The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma

Rationale: Protein palmitoylation is tightly related to tumorigenesis or tumor progression as many oncogenes or tumor suppressors are palmitoylated. AEG-1, an oncogene, is commonly elevated in a variety of human malignancies, including hepatocellular carcinoma (HCC). Although AEG-1 was suggested to...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhou, Binhui, Wang, Ying, Zhang, Lichen, Shi, Xiaoyi, Kong, Hesheng, Zhang, Mengjie, Liu, Yang, Shao, Xia, Liu, Zhilong, Song, Hongxu, Li, Wushan, Gao, Xiaoxi, Chang, Yanli, Dou, Chenzhuo, Guo, Wenzhi, Zhang, Shuijun, Kang, Xiaohong, Gao, Jie, Liang, Yinming, Zheng, Junfeng, Kong, Eryan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9576614/
https://www.ncbi.nlm.nih.gov/pubmed/36276642
http://dx.doi.org/10.7150/thno.78377
_version_ 1784811570497323008
author Zhou, Binhui
Wang, Ying
Zhang, Lichen
Shi, Xiaoyi
Kong, Hesheng
Zhang, Mengjie
Liu, Yang
Shao, Xia
Liu, Zhilong
Song, Hongxu
Li, Wushan
Gao, Xiaoxi
Chang, Yanli
Dou, Chenzhuo
Guo, Wenzhi
Zhang, Shuijun
Kang, Xiaohong
Gao, Jie
Liang, Yinming
Zheng, Junfeng
Kong, Eryan
author_facet Zhou, Binhui
Wang, Ying
Zhang, Lichen
Shi, Xiaoyi
Kong, Hesheng
Zhang, Mengjie
Liu, Yang
Shao, Xia
Liu, Zhilong
Song, Hongxu
Li, Wushan
Gao, Xiaoxi
Chang, Yanli
Dou, Chenzhuo
Guo, Wenzhi
Zhang, Shuijun
Kang, Xiaohong
Gao, Jie
Liang, Yinming
Zheng, Junfeng
Kong, Eryan
author_sort Zhou, Binhui
collection PubMed
description Rationale: Protein palmitoylation is tightly related to tumorigenesis or tumor progression as many oncogenes or tumor suppressors are palmitoylated. AEG-1, an oncogene, is commonly elevated in a variety of human malignancies, including hepatocellular carcinoma (HCC). Although AEG-1 was suggested to be potentially modified by protein palmitoylation, the regulatory roles of AEG-1 palmitoylation in tumor progression of HCC has not been explored. Methods: Techniques as Acyl-RAC assay and point mutation were used to confirm that AEG-1 is indeed palmitoylated. Moreover, biochemical experiments and immunofluorescent microscopy were applied to examine the cellular functions of AEG-1 palmitoylation in several cell lines. Remarkably, genetically modified knock-in (AEG-1-C75A) and knockout (Zdhhc6-KO) mice were established and subjected to the treatment of DEN to induce the HCC mice model, through which the roles of AEG-1 palmitoylation in HCC is directly addressed. Last, HCQ, a chemical compound, was introduced to prove in principal that elevating the level of AEG-1 palmitoylation might benefit the treatment of HCC in xenograft mouse model. Results: We showed that AEG-1 undergoes palmitoylation on a conserved cysteine residue, Cys-75. Blocking AEG-1 palmitoylation exacerbates the progression of DEN-induced HCC in vivo. Moreover, it was demonstrated that AEG-1 palmitoylation is dynamically regulated by zDHHC6 and PPT1/2. Accordingly, suppressing the level of AEG-1 palmitoylation by the deletion of Zdhhc6 reproduces the enhanced tumor-progression phenotype in DEN-induced HCC mouse model. Mechanistically, we showed that AEG-1 palmitoylation adversely regulates its protein stability and weakens AEG-1 and staphylococcal nuclease and tudor domain containing 1 (SND1) interaction, which might contribute to the alterations of the RISC activity and the expression of tumor suppressors. For intervention, HCQ, an inhibitor of PPT1, was applied to augment the level of AEG-1 palmitoylation, which retards the tumor growth of HCC in xenograft model. Conclusion: Our study suggests an unknown mechanism that AEG-1 palmitoylation dynamically manipulates HCC progression and pinpoints that raising AEG-1 palmitoylation might confer beneficial effect on the treatment of HCC.
format Online
Article
Text
id pubmed-9576614
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Ivyspring International Publisher
record_format MEDLINE/PubMed
spelling pubmed-95766142022-10-20 The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma Zhou, Binhui Wang, Ying Zhang, Lichen Shi, Xiaoyi Kong, Hesheng Zhang, Mengjie Liu, Yang Shao, Xia Liu, Zhilong Song, Hongxu Li, Wushan Gao, Xiaoxi Chang, Yanli Dou, Chenzhuo Guo, Wenzhi Zhang, Shuijun Kang, Xiaohong Gao, Jie Liang, Yinming Zheng, Junfeng Kong, Eryan Theranostics Research Paper Rationale: Protein palmitoylation is tightly related to tumorigenesis or tumor progression as many oncogenes or tumor suppressors are palmitoylated. AEG-1, an oncogene, is commonly elevated in a variety of human malignancies, including hepatocellular carcinoma (HCC). Although AEG-1 was suggested to be potentially modified by protein palmitoylation, the regulatory roles of AEG-1 palmitoylation in tumor progression of HCC has not been explored. Methods: Techniques as Acyl-RAC assay and point mutation were used to confirm that AEG-1 is indeed palmitoylated. Moreover, biochemical experiments and immunofluorescent microscopy were applied to examine the cellular functions of AEG-1 palmitoylation in several cell lines. Remarkably, genetically modified knock-in (AEG-1-C75A) and knockout (Zdhhc6-KO) mice were established and subjected to the treatment of DEN to induce the HCC mice model, through which the roles of AEG-1 palmitoylation in HCC is directly addressed. Last, HCQ, a chemical compound, was introduced to prove in principal that elevating the level of AEG-1 palmitoylation might benefit the treatment of HCC in xenograft mouse model. Results: We showed that AEG-1 undergoes palmitoylation on a conserved cysteine residue, Cys-75. Blocking AEG-1 palmitoylation exacerbates the progression of DEN-induced HCC in vivo. Moreover, it was demonstrated that AEG-1 palmitoylation is dynamically regulated by zDHHC6 and PPT1/2. Accordingly, suppressing the level of AEG-1 palmitoylation by the deletion of Zdhhc6 reproduces the enhanced tumor-progression phenotype in DEN-induced HCC mouse model. Mechanistically, we showed that AEG-1 palmitoylation adversely regulates its protein stability and weakens AEG-1 and staphylococcal nuclease and tudor domain containing 1 (SND1) interaction, which might contribute to the alterations of the RISC activity and the expression of tumor suppressors. For intervention, HCQ, an inhibitor of PPT1, was applied to augment the level of AEG-1 palmitoylation, which retards the tumor growth of HCC in xenograft model. Conclusion: Our study suggests an unknown mechanism that AEG-1 palmitoylation dynamically manipulates HCC progression and pinpoints that raising AEG-1 palmitoylation might confer beneficial effect on the treatment of HCC. Ivyspring International Publisher 2022-10-03 /pmc/articles/PMC9576614/ /pubmed/36276642 http://dx.doi.org/10.7150/thno.78377 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Zhou, Binhui
Wang, Ying
Zhang, Lichen
Shi, Xiaoyi
Kong, Hesheng
Zhang, Mengjie
Liu, Yang
Shao, Xia
Liu, Zhilong
Song, Hongxu
Li, Wushan
Gao, Xiaoxi
Chang, Yanli
Dou, Chenzhuo
Guo, Wenzhi
Zhang, Shuijun
Kang, Xiaohong
Gao, Jie
Liang, Yinming
Zheng, Junfeng
Kong, Eryan
The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma
title The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma
title_full The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma
title_fullStr The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma
title_full_unstemmed The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma
title_short The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma
title_sort palmitoylation of aeg-1 dynamically modulates the progression of hepatocellular carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9576614/
https://www.ncbi.nlm.nih.gov/pubmed/36276642
http://dx.doi.org/10.7150/thno.78377
work_keys_str_mv AT zhoubinhui thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT wangying thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT zhanglichen thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT shixiaoyi thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT konghesheng thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT zhangmengjie thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT liuyang thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT shaoxia thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT liuzhilong thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT songhongxu thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT liwushan thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT gaoxiaoxi thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT changyanli thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT douchenzhuo thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT guowenzhi thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT zhangshuijun thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT kangxiaohong thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT gaojie thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT liangyinming thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT zhengjunfeng thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT kongeryan thepalmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT zhoubinhui palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT wangying palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT zhanglichen palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT shixiaoyi palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT konghesheng palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT zhangmengjie palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT liuyang palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT shaoxia palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT liuzhilong palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT songhongxu palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT liwushan palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT gaoxiaoxi palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT changyanli palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT douchenzhuo palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT guowenzhi palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT zhangshuijun palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT kangxiaohong palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT gaojie palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT liangyinming palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT zhengjunfeng palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma
AT kongeryan palmitoylationofaeg1dynamicallymodulatestheprogressionofhepatocellularcarcinoma