Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer
Ortiz-Barahona, Vanessa (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Soler, Marta (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Davalos, Veronica (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
García-Prieto, Carlos A. (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Janin, Maxime (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Setien, Fernando (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Fernández-Rebollo, Irene (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Bech-Serra, Joan J. (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
De La Torre, Carolina (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Guil, Sonia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Villanueva, Alberto (Institut d'Investigació Biomèdica de Bellvitge)
Zhang, Pei Hong (Fudan University, Shanghai, China)
Yang, Li (Fudan University, Shanghai, China)
Guarnacci, Marco (Australian National University, Canberra, Australia)
Schumann, Ulrike (Australian National University, Canberra, Australia)
Preiss, Thomas (Australian National University, Canberra, Australia)
Balaseviciute, Ugne (Hospital Clínic i Provincial de Barcelona)
Montal, Robert (Universitat de Lleida)
Llovet, Josep M. (Hospital Clínic i Provincial de Barcelona)
Esteller, Manel (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)

Data:	2023
Resum:	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.
Ajuts:	Instituto de Salud Carlos III PI19/01320 Agencia Estatal de Investigación PID2021-125282OB-I00
Nota:	Altres ajuts: The Australian National Medical Research Council (APP1061551, APP1135928) and the Australian Research Council (DP210102385)
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	RNA modifications ; 5-methylcytosine RNA methyltransferase ; NSUN7 ; Epigenetics ; DNA methylation ; Liver cancer
Publicat a:	Molecular cancer, Vol. 22 Núm. 1 (may 2023) , ISSN 1476-4598

DOI: 10.1186/s12943-023-01785-z
PMID: 37173708

15 p, 4.7 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Institut de Recerca contra la Leucèmia Josep Carreras
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