MAZ-mediated N6-methyladenosine modification of ZEB1 promotes hepatocellular carcinoma progression by regulating METTL3
Abstract Background Hepatocellular carcinoma (HCC) has a hidden onset and high malignancy. Its high metastasis, high recurrence, and short survival time have always been a difficult and hot spot in clinical practice. Our previous study revealed that myc-associated zinc finger protein (MAZ) is highly...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-03-01
|
| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-025-06314-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850251802535002112 |
|---|---|
| author | Di Li Li Xu Ruyuan Liu Zhaonv Yao Chuanjun Zheng Song Jin Xuefeng Guo Zhengbao Zhang Shengkui Tan Xiaonian Zhu |
| author_facet | Di Li Li Xu Ruyuan Liu Zhaonv Yao Chuanjun Zheng Song Jin Xuefeng Guo Zhengbao Zhang Shengkui Tan Xiaonian Zhu |
| author_sort | Di Li |
| collection | DOAJ |
| description | Abstract Background Hepatocellular carcinoma (HCC) has a hidden onset and high malignancy. Its high metastasis, high recurrence, and short survival time have always been a difficult and hot spot in clinical practice. Our previous study revealed that myc-associated zinc finger protein (MAZ) is highly upregulated in HCC tissues and may promote the proliferation and metastasis of HCC cells by inducing the epithelial-mesenchymal transformation (EMT) process. However, the specific regulatory mechanism by which MAZ functions as an oncogene in HCC has still not been fully elucidated. Methods Immunohistochemical staining and bioinformatics analyses were conducted to measure the expression of MAZ, key m6A enzymes, and ZEB1 in HCC tissues. RNA sequencing (RNA-seq) of MAZ knockdown HCC cells and human mRNA m6A sequencing (m6A-seq) of HCC tissues were intersected to screen the downstream targets for both MAZ and m6A methylation. The correlations between MAZ and its targets were analyzed by dual-luciferase assays and cell rescue experiments. Results Here, we report for the first time that MAZ is involved in m6A methylation of HCC by targeting the transcriptional regulation of key m6A enzymes. MAZ expression was significantly correlated with the expression of key m6A enzymes in HCC tissues and cell lines. Moreover, MAZ could bind to the promoters of key m6A enzymes, and multivariate Cox regression analysis suggested that MAZ and METTL3 expression were independent risk factors for the survival of HCC patients. Through RNA-seq and m6A-seq, we screened out EMT regulators ZEB1 and TRIM50 as the downstream targets for both MAZ and m6A methylation. Mechanistically, m6A sites with high confidence in ZEB1 and TRIM50 mRNA were identified by SRAMP, and there were significant relationships between ZEB1 and METTL3 in HCC tissues and cells. A nomogram model was established to better display the combined effect of MAZ, METTL3, and ZEB1 on HCC prognosis. Conclusions Our study revealed a promising clinical application of MAZ, METTL3, and ZEB1 in HCC prognosis, further suggesting that MAZ can be used as a potential molecular biomarker for HCC diagnosis and prognosis. |
| format | Article |
| id | doaj-art-4a9140bcb8c245f08ccd68745db8e30b |
| institution | OA Journals |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-4a9140bcb8c245f08ccd68745db8e30b2025-08-20T01:57:49ZengBMCJournal of Translational Medicine1479-58762025-03-0123111510.1186/s12967-025-06314-8MAZ-mediated N6-methyladenosine modification of ZEB1 promotes hepatocellular carcinoma progression by regulating METTL3Di Li0Li Xu1Ruyuan Liu2Zhaonv Yao3Chuanjun Zheng4Song Jin5Xuefeng Guo6Zhengbao Zhang7Shengkui Tan8Xiaonian Zhu9Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical UniversityGuangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical UniversityGuangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical UniversityGuangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical UniversityGuangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical UniversityGuangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical UniversityGuangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical UniversityGuangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical UniversityGuangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical UniversityGuangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical UniversityAbstract Background Hepatocellular carcinoma (HCC) has a hidden onset and high malignancy. Its high metastasis, high recurrence, and short survival time have always been a difficult and hot spot in clinical practice. Our previous study revealed that myc-associated zinc finger protein (MAZ) is highly upregulated in HCC tissues and may promote the proliferation and metastasis of HCC cells by inducing the epithelial-mesenchymal transformation (EMT) process. However, the specific regulatory mechanism by which MAZ functions as an oncogene in HCC has still not been fully elucidated. Methods Immunohistochemical staining and bioinformatics analyses were conducted to measure the expression of MAZ, key m6A enzymes, and ZEB1 in HCC tissues. RNA sequencing (RNA-seq) of MAZ knockdown HCC cells and human mRNA m6A sequencing (m6A-seq) of HCC tissues were intersected to screen the downstream targets for both MAZ and m6A methylation. The correlations between MAZ and its targets were analyzed by dual-luciferase assays and cell rescue experiments. Results Here, we report for the first time that MAZ is involved in m6A methylation of HCC by targeting the transcriptional regulation of key m6A enzymes. MAZ expression was significantly correlated with the expression of key m6A enzymes in HCC tissues and cell lines. Moreover, MAZ could bind to the promoters of key m6A enzymes, and multivariate Cox regression analysis suggested that MAZ and METTL3 expression were independent risk factors for the survival of HCC patients. Through RNA-seq and m6A-seq, we screened out EMT regulators ZEB1 and TRIM50 as the downstream targets for both MAZ and m6A methylation. Mechanistically, m6A sites with high confidence in ZEB1 and TRIM50 mRNA were identified by SRAMP, and there were significant relationships between ZEB1 and METTL3 in HCC tissues and cells. A nomogram model was established to better display the combined effect of MAZ, METTL3, and ZEB1 on HCC prognosis. Conclusions Our study revealed a promising clinical application of MAZ, METTL3, and ZEB1 in HCC prognosis, further suggesting that MAZ can be used as a potential molecular biomarker for HCC diagnosis and prognosis.https://doi.org/10.1186/s12967-025-06314-8MAZm6A methylationHCCEMTZEB1 |
| spellingShingle | Di Li Li Xu Ruyuan Liu Zhaonv Yao Chuanjun Zheng Song Jin Xuefeng Guo Zhengbao Zhang Shengkui Tan Xiaonian Zhu MAZ-mediated N6-methyladenosine modification of ZEB1 promotes hepatocellular carcinoma progression by regulating METTL3 Journal of Translational Medicine MAZ m6A methylation HCC EMT ZEB1 |
| title | MAZ-mediated N6-methyladenosine modification of ZEB1 promotes hepatocellular carcinoma progression by regulating METTL3 |
| title_full | MAZ-mediated N6-methyladenosine modification of ZEB1 promotes hepatocellular carcinoma progression by regulating METTL3 |
| title_fullStr | MAZ-mediated N6-methyladenosine modification of ZEB1 promotes hepatocellular carcinoma progression by regulating METTL3 |
| title_full_unstemmed | MAZ-mediated N6-methyladenosine modification of ZEB1 promotes hepatocellular carcinoma progression by regulating METTL3 |
| title_short | MAZ-mediated N6-methyladenosine modification of ZEB1 promotes hepatocellular carcinoma progression by regulating METTL3 |
| title_sort | maz mediated n6 methyladenosine modification of zeb1 promotes hepatocellular carcinoma progression by regulating mettl3 |
| topic | MAZ m6A methylation HCC EMT ZEB1 |
| url | https://doi.org/10.1186/s12967-025-06314-8 |
| work_keys_str_mv | AT dili mazmediatedn6methyladenosinemodificationofzeb1promoteshepatocellularcarcinomaprogressionbyregulatingmettl3 AT lixu mazmediatedn6methyladenosinemodificationofzeb1promoteshepatocellularcarcinomaprogressionbyregulatingmettl3 AT ruyuanliu mazmediatedn6methyladenosinemodificationofzeb1promoteshepatocellularcarcinomaprogressionbyregulatingmettl3 AT zhaonvyao mazmediatedn6methyladenosinemodificationofzeb1promoteshepatocellularcarcinomaprogressionbyregulatingmettl3 AT chuanjunzheng mazmediatedn6methyladenosinemodificationofzeb1promoteshepatocellularcarcinomaprogressionbyregulatingmettl3 AT songjin mazmediatedn6methyladenosinemodificationofzeb1promoteshepatocellularcarcinomaprogressionbyregulatingmettl3 AT xuefengguo mazmediatedn6methyladenosinemodificationofzeb1promoteshepatocellularcarcinomaprogressionbyregulatingmettl3 AT zhengbaozhang mazmediatedn6methyladenosinemodificationofzeb1promoteshepatocellularcarcinomaprogressionbyregulatingmettl3 AT shengkuitan mazmediatedn6methyladenosinemodificationofzeb1promoteshepatocellularcarcinomaprogressionbyregulatingmettl3 AT xiaonianzhu mazmediatedn6methyladenosinemodificationofzeb1promoteshepatocellularcarcinomaprogressionbyregulatingmettl3 |