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N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we show that N(1)-methyladenosine methylation (m(1)A) in tRNA is remarkably elevated in hepatocellular carcinoma...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563902/ https://www.ncbi.nlm.nih.gov/pubmed/34728628 http://dx.doi.org/10.1038/s41467-021-26718-6 |
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author | Wang, Yanying Wang, Jing Li, Xiaoyu Xiong, Xushen Wang, Jianyi Zhou, Ziheng Zhu, Xiaoxiao Gu, Yang Dominissini, Dan He, Lei Tian, Yong Yi, Chengqi Fan, Zusen |
author_facet | Wang, Yanying Wang, Jing Li, Xiaoyu Xiong, Xushen Wang, Jianyi Zhou, Ziheng Zhu, Xiaoxiao Gu, Yang Dominissini, Dan He, Lei Tian, Yong Yi, Chengqi Fan, Zusen |
author_sort | Wang, Yanying |
collection | PubMed |
description | Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we show that N(1)-methyladenosine methylation (m(1)A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m(1)A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m(1)A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m(1)A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m(1)A methylation in a subset of tRNA to increase PPARδ translation, which in turn triggers cholesterol synthesis to activate Hedgehog signaling, eventually driving self-renewal of liver CSCs and tumourigenesis. Finally, we identify a potent inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer. |
format | Online Article Text |
id | pubmed-8563902 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85639022021-11-19 N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism Wang, Yanying Wang, Jing Li, Xiaoyu Xiong, Xushen Wang, Jianyi Zhou, Ziheng Zhu, Xiaoxiao Gu, Yang Dominissini, Dan He, Lei Tian, Yong Yi, Chengqi Fan, Zusen Nat Commun Article Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we show that N(1)-methyladenosine methylation (m(1)A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m(1)A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m(1)A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m(1)A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m(1)A methylation in a subset of tRNA to increase PPARδ translation, which in turn triggers cholesterol synthesis to activate Hedgehog signaling, eventually driving self-renewal of liver CSCs and tumourigenesis. Finally, we identify a potent inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer. Nature Publishing Group UK 2021-11-02 /pmc/articles/PMC8563902/ /pubmed/34728628 http://dx.doi.org/10.1038/s41467-021-26718-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Wang, Yanying Wang, Jing Li, Xiaoyu Xiong, Xushen Wang, Jianyi Zhou, Ziheng Zhu, Xiaoxiao Gu, Yang Dominissini, Dan He, Lei Tian, Yong Yi, Chengqi Fan, Zusen N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism |
title | N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism |
title_full | N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism |
title_fullStr | N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism |
title_full_unstemmed | N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism |
title_short | N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism |
title_sort | n(1)-methyladenosine methylation in trna drives liver tumourigenesis by regulating cholesterol metabolism |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563902/ https://www.ncbi.nlm.nih.gov/pubmed/34728628 http://dx.doi.org/10.1038/s41467-021-26718-6 |
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