Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program

被引：137

作者：

Janin, Maxime ^{[1
]}

Ortiz-Barahona, Vanessa ^{[1
]}

de Moura, Manuel Castro ^{[1
]}

Martinez-Cardus, Anna ^{[1
]}

Llinas-Arias, Pere ^{[1
]}

Soler, Marta ^{[1
]}

Nachmani, Daphna ^{[2
]}

Pelletier, Joffrey ^{[3
]}

Schumann, Ulrike ^{[4
]}

Calleja-Cervantes, Maria E. ^{[1
]}

Moran, Sebastian ^{[1
]}

Guil, Sonia ^{[1
]}

Bueno-Costa, Alberto ^{[1
]}

Pineyro, David ^{[1
]}

Perez-Salvia, Montserrat ^{[1
]}

Rossello-Tortella, Margalida ^{[1
]}

Pique, Laia ^{[1
]}

Bech-Serra, Joan J. ^{[5
]}

De la Torre, Carolina ^{[5
]}

Vidal, August ^{[6
,7
]}

Martinez-Iniesta, Maria ^{[8
]}

Martin-Tejera, Juan F. ^{[8
]}

Villanueva, Alberto ^{[8
]}

Arias, Alexandra ^{[9
]}

Cuartas, Isabel ^{[9
]}

Aransay, Ana M. ^{[10
]}

La Madrid, Andres Morales ^{[11
,12
]}

Carcaboso, Angel M. ^{[13
]}

Santa-Maria, Vicente ^{[11
,12
]}

Mora, Jaume ^{[11
]}

Fernandez, Agustin F. ^{[14
]}

Fraga, Mario F. ^{[15
]}

Aldecoa, Iban ^{[16
]}

Pedrosa, Leire ^{[17
,18
]}

Graus, Francesc ^{[19
]}

Vidal, Noemi ^{[6
]}

Martinez-Soler, Fina ^{[20
]}

Tortosa, Avelina ^{[20
]}

Carrato, Cristina ^{[21
]}

Balana, Carme ^{[22
]}

Boudreau, Matthew W. ^{[23
]}

Hergenrother, Paul J. ^{[23
]}

Koetter, Peter ^{[24
]}

Entian, Karl-Dieter ^{[24
]}

Hench, Juergen ^{[25
]}

Frank, Stephan ^{[25
]}

Mansouri, Sheila ^{[26
]}

Zadeh, Gelareh ^{[26
]}

Dans, Pablo D. ^{[27
]}

Orozco, Modesto ^{[27
,28
]}

机构：

[1] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona, Catalonia, Spain

[2] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Canc Res Inst, Dept Med & Pathol, Boston, MA 02115 USA

[3] Bellvitge Biomed Res Inst IDIBELL, Metab & Canc Grp, Mol Mech & Expt Therapy Oncol Program, Barcelona, Catalonia, Spain

[4] Australian Natl Univ, John Curtin Sch Med Res, Dept Genome Sci, EMBL Australia Collaborating Grp, Garran Rd, Acton, ACT 2601, Australia

[5] Bellvitge Biomed Res Inst IDIBELL, Prote Unit, Barcelona, Catalonia, Spain

[6] Hosp Univ Bellvitge, Dept Pathol, IDIBELL, Barcelona, Catalonia, Spain

[7] Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain

[8] Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Oncobell Program, Program Canc Therapeut Resistance ProCURE, Barcelona, Catalonia, Spain

[9] Univ Autonoma Barcelona, Vall dHebron Univ Hosp, Vall dHebron Inst Oncol VHIO, Barcelona, Catalonia, Spain

[10] CIC BioGUNE, Ctr Invest Bimed Red Enfermedades Hepat & Digest, 801A Bizkaia Technol Pk, Derio 48160, Spain

[11] Hosp St Joan de Deu, Dept Pediat Hematol & Oncol, Barcelona, Catalonia, Spain

[12] Hosp St Joan de Deu, Dept Pediat Hematol & Oncol, Pediat Neurooncol Unit, Barcelona, Catalonia, Spain

[13] Fundacio St Joan de Deu, Preclin Therapeut & Drug Delivery Res Program, Barcelona, Catalonia, Spain

[14] Inst Invest Sanitaria Principado Asturias ISPA FI, Inst Oncol Asturias IUOPA, Oviedo 33011, Spain

[15] Univ Oviedo Principado Asturias, Nanomat & Nanotechnol Res Ctr CINN CSIC, Oviedo, Spain

[16] August Pi & Sunyer Biomed Res Inst IDIBAPS, CDB, Hosp Clin Barcelona, Pathol Brain Bank, Barcelona, Catalonia, Spain

[17] IDIBAPS, Glioma & Neural Stem Cell Grp, Barcelona, Catalonia, Spain

[18] IDIBAPS, Translat Genom & Targeted Therapeut Solid Tumors, Barcelona, Catalonia, Spain

[19] IDIBAPS, Clin & Expt Neuroimmunol, Barcelona, Catalonia, Spain

[20] Univ Barcelona, Fac Med & Hlth Sci Bellvitge, IDIBELL, Barcelona, Catalonia, Spain

[21] Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, Dept Pathol, Badalona, Catalonia, Spain

[22] Hosp Badalona Germans Trias & Pujol, Catalan Inst Oncol, Badalona 08916, Catalonia, Spain

[23] Univ Illinois, Dept Chem, Urbana, IL 61801 USA

[24] Goethe Univ, Inst Mol Biosci, Frankfurt, Germany

[25] Univ Hosp Basel, Inst Med Genet & Pathol, Div Neuropathol, CH-4031 Basel, Switzerland

[26] Univ Toronto, Toronto Western Hosp, Div Neurosurg, Toronto, ON, Canada

[27] Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Joint IRB BSC Program Computat Biol, Barcelona 08028, Catalonia, Spain

[28] Univ Barcelona, Dept Biochem & Biomed, E-08028 Barcelona, Spain

[29] Univ Barcelona, Sch Med & Hlth Sci, Physiol Sci Dept, Barcelona, Catalonia, Spain

[30] Univ Cincinnati, Dept Internal Med, Div Hematol Oncol, Med Sch, Cincinnati, OH 45267 USA

[31] CIC BioGUNE, 801A Bizkaia Technol Pk, Derio 48160, Spain

[32] Univ Salamanca, CSIC, Ctr Invest Canc, Mol Mech Program, Salamanca 37007, Spain

[33] Univ Salamanca, CSIC, Inst Biol Mol & Celular Canc, Salamanca 37007, Spain

[34] ICREA, Barcelona, Catalonia, Spain

[35] Victor Chang Cardiac Res Inst, Sydney, NSW 2010, Australia

[36] Josep Carreras Leukaemia Res Inst IJC, Ctra Can Ruti,Cami Escoles S-N, Barcelona 08916, Catalonia, Spain

来源：

ACTA NEUROPATHOLOGICA | 2019年 / 138卷 / 06期

关键词：

Glioma; Epitranscriptomics; RNA methylation; Clinical outcome; DYSKERATOSIS-CONGENITA; CANCER; GENE; METHYLATION; MUTATIONS; BINDING; GENOME; YEAST; MGMT;

D O I：

10.1007/s00401-019-02062-4

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.

引用

页码：1053 / 1074

页数：22

共 4 条

[1] Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program
Maxime Janin
Vanessa Ortiz-Barahona
Manuel Castro de Moura
Anna Martínez-Cardús
Pere Llinàs-Arias
Marta Soler
Daphna Nachmani
Joffrey Pelletier
Ulrike Schumann
Maria E. Calleja-Cervantes
Sebastian Moran
Sonia Guil
Alberto Bueno-Costa
David Piñeyro
Montserrat Perez-Salvia
Margalida Rosselló-Tortella
Laia Piqué
Joan J. Bech-Serra
Carolina De La Torre
August Vidal
María Martínez-Iniesta
Juan F. Martín-Tejera
Alberto Villanueva
Alexandra Arias
Isabel Cuartas
Ana M. Aransay
Andres Morales La Madrid
Angel M. Carcaboso
Vicente Santa-Maria
Jaume Mora
Agustin F. Fernandez
Mario F. Fraga
Iban Aldecoa
Leire Pedrosa
Francesc Graus
Noemi Vidal
Fina Martínez-Soler
Avelina Tortosa
Cristina Carrato
Carme Balañá
Matthew W. Boudreau
Paul J. Hergenrother
Peter Kötter
Karl-Dieter Entian
Jürgen Hench
Stephan Frank
Sheila Mansouri
Gelareh Zadeh
Pablo D. Dans
Modesto Orozco
Acta Neuropathologica, 2019, 138 : 1053 - 1074
[2] Epigenetic loss of NSUN5 in glioma drives a global protein synthesis depletion along with the emergence of a stress adaptive translational program
Ortiz Barahona, Vanessa
Janin, Maxime
Esteller, Manel
CANCER RESEARCH, 2020, 80 (16)
[3] RNA-methyltransferase Nsun5 controls the maternal-to-zygotic transition by regulating maternal mRNA stability
Ding, Chenyue
Lu, Jiafeng
Li, Jincheng
Hu, Xiujuan
Liu, Zhenxing
Su, Han
Li, Hong
Huang, Boxian
CLINICAL AND TRANSLATIONAL MEDICINE, 2022, 12 (12):
[4] Loss of the ribosomal RNA methyltransferase NSUN5 impairs global protein synthesis and normal growth
Heissenberger, Clemens
Liendl, Lisa
Nagelreiter, Fabian
Gonskikh, Yulia
Yang, Guohuan
Stelzer, Elena M.
Krammer, Teresa L.
Micutkova, Lucia
Vogt, Stefan
Kreil, David P.
Sekot, Gerhard
Siena, Emilio
Poser, Ina
Harreither, Eva
Linder, Angela
Ehret, Viktoria
Helbich, Thomas H.
Grillari-Voglauer, Regina
Jansen-Duerr, Pidder
Kos, Martin
Polacek, Norbert
Grillari, Johannes
Schosserer, Markus
NUCLEIC ACIDS RESEARCH, 2019, 47 (22) : 11807 - 11825

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