DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334
Abstract DNA methylation plays a pivotal role in the development and progression of tumors. However, studies focused on the dynamic changes of DNA methylation in the development of hepatocellular carcinoma (HCC) are rare. To systematically illustrate the dynamic DNA methylation alternation from prem...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-05-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04895-6 |
| _version_ | 1811252156461744128 |
|---|---|
| author | Dapeng Sun Xiaojie Gan Lei Liu Yuan Yang Dongyang Ding Wen Li Junyao Jiang Wenbin Ding Linghao Zhao Guojun Hou Jian Yu Jie Wang Fu Yang Shengxian Yuan Weiping Zhou |
| author_facet | Dapeng Sun Xiaojie Gan Lei Liu Yuan Yang Dongyang Ding Wen Li Junyao Jiang Wenbin Ding Linghao Zhao Guojun Hou Jian Yu Jie Wang Fu Yang Shengxian Yuan Weiping Zhou |
| author_sort | Dapeng Sun |
| collection | DOAJ |
| description | Abstract DNA methylation plays a pivotal role in the development and progression of tumors. However, studies focused on the dynamic changes of DNA methylation in the development of hepatocellular carcinoma (HCC) are rare. To systematically illustrate the dynamic DNA methylation alternation from premalignant to early-stage liver cancer with the same genetic background, this study enrolled 5 HBV-related patients preceded with liver cirrhosis, pathologically identified as early-stage HCC with dysplastic nodules. Liver fibrosis tissues, dysplastic nodules and early HCC tissues from these patients were used to measure DNA methylation. Here, we report significant differences in the DNA methylation spectrum among the three types of tissues. In the early stage of HCC, DNA hypermethylation of tumor suppressor genes is predominant. Additionally, DNA hypermethylation in the early stage of HCC changes the binding ability of transcription factor TP53 to the promoter of tumor suppressor gene ZNF334, and inhibits the expression of ZNF334 at the transcription level. Furthermore, through a series of in vivo and in vitro experiments, we have clarified the exacerbation effect of tumor suppressor gene ZNF334 deletion in the occurrence of HCC. Combined with clinical data, we found that the overall survival and relapse-free survival of patients with high ZNF334 expression are significantly longer. Thus, we partly elucidated a sequential alternation of DNA methylation modification during the occurrence of HCC, and clarified the biological function and regulatory mechanism of the tumor suppressor gene ZNF334, which is regulated by related DNA methylation sites. Our study provides a new target and clinical evidence for the early diagnosis and sheds light on the precise treatment of liver cancer. |
| first_indexed | 2024-04-12T16:30:41Z |
| format | Article |
| id | doaj.art-febc9e9e42ac46f68481b4f26287a861 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T16:30:41Z |
| publishDate | 2022-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-febc9e9e42ac46f68481b4f26287a8612022-12-22T03:25:09ZengNature Publishing GroupCell Death and Disease2041-48892022-05-0113511210.1038/s41419-022-04895-6DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334Dapeng Sun0Xiaojie Gan1Lei Liu2Yuan Yang3Dongyang Ding4Wen Li5Junyao Jiang6Wenbin Ding7Linghao Zhao8Guojun Hou9Jian Yu10Jie Wang11Fu Yang12Shengxian Yuan13Weiping Zhou14The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityCenter for Health Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityCenter for Health Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesThe department of Medical Genetics, Naval Medical UniversityThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityThe Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical UniversityAbstract DNA methylation plays a pivotal role in the development and progression of tumors. However, studies focused on the dynamic changes of DNA methylation in the development of hepatocellular carcinoma (HCC) are rare. To systematically illustrate the dynamic DNA methylation alternation from premalignant to early-stage liver cancer with the same genetic background, this study enrolled 5 HBV-related patients preceded with liver cirrhosis, pathologically identified as early-stage HCC with dysplastic nodules. Liver fibrosis tissues, dysplastic nodules and early HCC tissues from these patients were used to measure DNA methylation. Here, we report significant differences in the DNA methylation spectrum among the three types of tissues. In the early stage of HCC, DNA hypermethylation of tumor suppressor genes is predominant. Additionally, DNA hypermethylation in the early stage of HCC changes the binding ability of transcription factor TP53 to the promoter of tumor suppressor gene ZNF334, and inhibits the expression of ZNF334 at the transcription level. Furthermore, through a series of in vivo and in vitro experiments, we have clarified the exacerbation effect of tumor suppressor gene ZNF334 deletion in the occurrence of HCC. Combined with clinical data, we found that the overall survival and relapse-free survival of patients with high ZNF334 expression are significantly longer. Thus, we partly elucidated a sequential alternation of DNA methylation modification during the occurrence of HCC, and clarified the biological function and regulatory mechanism of the tumor suppressor gene ZNF334, which is regulated by related DNA methylation sites. Our study provides a new target and clinical evidence for the early diagnosis and sheds light on the precise treatment of liver cancer.https://doi.org/10.1038/s41419-022-04895-6 |
| spellingShingle | Dapeng Sun Xiaojie Gan Lei Liu Yuan Yang Dongyang Ding Wen Li Junyao Jiang Wenbin Ding Linghao Zhao Guojun Hou Jian Yu Jie Wang Fu Yang Shengxian Yuan Weiping Zhou DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334 Cell Death and Disease |
| title | DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334 |
| title_full | DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334 |
| title_fullStr | DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334 |
| title_full_unstemmed | DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334 |
| title_short | DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334 |
| title_sort | dna hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene znf334 |
| url | https://doi.org/10.1038/s41419-022-04895-6 |
| work_keys_str_mv | AT dapengsun dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT xiaojiegan dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT leiliu dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT yuanyang dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT dongyangding dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT wenli dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT junyaojiang dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT wenbinding dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT linghaozhao dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT guojunhou dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT jianyu dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT jiewang dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT fuyang dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT shengxianyuan dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 AT weipingzhou dnahypermethylationmodificationpromotesthedevelopmentofhepatocellularcarcinomabydepressingthetumorsuppressorgeneznf334 |