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Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer
BACKGROUND: RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. METHODS: Combining data mining and conventional experimental procedures, NSUN7 methylatio...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10176850/ https://www.ncbi.nlm.nih.gov/pubmed/37173708 http://dx.doi.org/10.1186/s12943-023-01785-z |
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author | Ortiz-Barahona, Vanessa Soler, Marta Davalos, Veronica García-Prieto, Carlos A. Janin, Maxime Setien, Fernando Fernández-Rebollo, Irene Bech-Serra, Joan J. De La Torre, Carolina Guil, Sonia Villanueva, Alberto Zhang, Pei-Hong Yang, Li Guarnacci, Marco Schumann, Ulrike Preiss, Thomas Balaseviciute, Ugne Montal, Robert Llovet, Josep M. Esteller, Manel |
author_facet | Ortiz-Barahona, Vanessa Soler, Marta Davalos, Veronica García-Prieto, Carlos A. Janin, Maxime Setien, Fernando Fernández-Rebollo, Irene Bech-Serra, Joan J. De La Torre, Carolina Guil, Sonia Villanueva, Alberto Zhang, Pei-Hong Yang, Li Guarnacci, Marco Schumann, Ulrike Preiss, Thomas Balaseviciute, Ugne Montal, Robert Llovet, Josep M. Esteller, Manel |
author_sort | Ortiz-Barahona, Vanessa |
collection | PubMed |
description | BACKGROUND: RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. METHODS: Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cancer cell lines and primary tumors. Loss-of-function and transfection-mediated recovery experiments coupled with RNA bisulfite sequencing and proteomics determined the activity of NSUN7 in downstream targets and drug sensitivity. RESULTS: In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in transformed cell lines, identified that the NOL1/NOP2/Sun domain family member 7 (NSUN7) undergoes promoter CpG island hypermethylation-associated with transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to find the RNA targets of this poorly characterized putative RNA methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript stability. Most importantly, proteomic analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival. Interestingly, NSUN7 unmethylated status was enriched in the immune active subclass of liver tumors. CONCLUSION: The 5-methylcytosine RNA methyltransferase NSUN7 undergoes epigenetic inactivation in liver cancer that prevents correct mRNA methylation. Furthermore, NSUN7 DNA methylation-associated silencing is associated with clinical outcome and distinct therapeutic vulnerability. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-023-01785-z. |
format | Online Article Text |
id | pubmed-10176850 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-101768502023-05-13 Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer Ortiz-Barahona, Vanessa Soler, Marta Davalos, Veronica García-Prieto, Carlos A. Janin, Maxime Setien, Fernando Fernández-Rebollo, Irene Bech-Serra, Joan J. De La Torre, Carolina Guil, Sonia Villanueva, Alberto Zhang, Pei-Hong Yang, Li Guarnacci, Marco Schumann, Ulrike Preiss, Thomas Balaseviciute, Ugne Montal, Robert Llovet, Josep M. Esteller, Manel Mol Cancer Research BACKGROUND: RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. METHODS: Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cancer cell lines and primary tumors. Loss-of-function and transfection-mediated recovery experiments coupled with RNA bisulfite sequencing and proteomics determined the activity of NSUN7 in downstream targets and drug sensitivity. RESULTS: In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in transformed cell lines, identified that the NOL1/NOP2/Sun domain family member 7 (NSUN7) undergoes promoter CpG island hypermethylation-associated with transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to find the RNA targets of this poorly characterized putative RNA methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript stability. Most importantly, proteomic analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival. Interestingly, NSUN7 unmethylated status was enriched in the immune active subclass of liver tumors. CONCLUSION: The 5-methylcytosine RNA methyltransferase NSUN7 undergoes epigenetic inactivation in liver cancer that prevents correct mRNA methylation. Furthermore, NSUN7 DNA methylation-associated silencing is associated with clinical outcome and distinct therapeutic vulnerability. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-023-01785-z. BioMed Central 2023-05-12 /pmc/articles/PMC10176850/ /pubmed/37173708 http://dx.doi.org/10.1186/s12943-023-01785-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Ortiz-Barahona, Vanessa Soler, Marta Davalos, Veronica García-Prieto, Carlos A. Janin, Maxime Setien, Fernando Fernández-Rebollo, Irene Bech-Serra, Joan J. De La Torre, Carolina Guil, Sonia Villanueva, Alberto Zhang, Pei-Hong Yang, Li Guarnacci, Marco Schumann, Ulrike Preiss, Thomas Balaseviciute, Ugne Montal, Robert Llovet, Josep M. Esteller, Manel Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer |
title | Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer |
title_full | Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer |
title_fullStr | Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer |
title_full_unstemmed | Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer |
title_short | Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer |
title_sort | epigenetic inactivation of the 5-methylcytosine rna methyltransferase nsun7 is associated with clinical outcome and therapeutic vulnerability in liver cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10176850/ https://www.ncbi.nlm.nih.gov/pubmed/37173708 http://dx.doi.org/10.1186/s12943-023-01785-z |
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