METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer
Raquel García-Vílchez
(1, 2)
,
Ana Añazco-Guenkova
(1, 2)
,
Sabine Dietmann
(3)
,
Judith López
(1, 2)
,
Virginia Morón-Calvente
(1, 2)
,
Silvia D’ambrosi
(4, 5)
,
Paz Nombela
(1, 2)
,
Kepa Zamacola
(4, 5)
,
Isabel Mendizabal
(4, 5, 6)
,
Saioa García-Longarte
(4, 5)
,
Amaia Zabala-Letona
(4, 5, 7)
,
Ianire Astobiza
(4, 5, 7)
,
Sonia Fernández
(4, 5, 7)
,
Alejandro Paniagua
(1)
,
Borja Miguel-López
(1, 2)
,
Virginie Marchand
(8)
,
Diego Alonso-López
(1)
,
Angelika Merkel
(9, 10)
,
Ignacio García-Tuñón
(1)
,
Aitziber Ugalde-Olano
,
Ana Loizaga-Iriarte
(7, 11)
,
Isabel Lacasa-Viscasillas
,
Miguel Unda
(7, 11)
,
Mikel Azkargorta
(4, 5)
,
Félix Elortza
(4, 5, 12)
,
Laura Bárcena
(4, 5)
,
Monika Gonzalez-Lopez
(4, 5)
,
Ana Aransay
(4, 5, 12)
,
Tomás Di Domenico
(13)
,
Manuel Sánchez-Martín
(2, 1)
,
Javier de las Rivas
(1)
,
Sònia Guil
(9, 14)
,
Yuri Motorin
(8, 15)
,
Mark Helm
(16)
,
Pier Paolo Pandolfi
(17, 18)
,
Arkaitz Carracedo
(4, 5, 6, 7, 19)
,
Sandra Blanco
(1, 2, 4, 5)
1
Universidad de Salamanca [España] = University of Salamanca [Spain]
2 IBSAL - Instituto de Investigación Biomédica de Salamanca
3 Washington University School of Medicine in St. Louis
4 CIC bioGUNE - Center for Cooperative Research in Biosciences = Centro de Investigación cooperativa en biociencia (Derio, Biscay, Espagne)
5 BRTA - Basque Research and Technology Alliance
6 Ikerbasque - Basque Foundation for Science
7 CIBERONC - Centro de Investigación Biomédica en Red de Cáncer
8 IBSLor - Ingénierie, Biologie et Santé en Lorraine
9 IJC - Josep Carreras Leukaemia Research Institute
10 IGTP - Institut d’Investigació Germans Trias i Pujol = Germans Trias i Pujol Research Institute
11 Biocruces Bizkaia Health Research Institute [Baracaldo]
12 CIBERehd - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
13 CNIO - Centro Nacional de Investigaciones Oncologicas / Spanish National Cancer Research Centre [Madrid, Espagne]
14 GTPUH - Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain]
15 IMoPA - Ingénierie Moléculaire et Physiopathologie Articulaire
16 JGU - Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University
17 UNITO - Università degli studi di Torino = University of Turin
18 NSHE - Nevada System of Higher Education
19 UPV / EHU - Universidad del País Vasco [Espainia] / Euskal Herriko Unibertsitatea [España] = University of the Basque Country [Spain] = Université du pays basque [Espagne]
2 IBSAL - Instituto de Investigación Biomédica de Salamanca
3 Washington University School of Medicine in St. Louis
4 CIC bioGUNE - Center for Cooperative Research in Biosciences = Centro de Investigación cooperativa en biociencia (Derio, Biscay, Espagne)
5 BRTA - Basque Research and Technology Alliance
6 Ikerbasque - Basque Foundation for Science
7 CIBERONC - Centro de Investigación Biomédica en Red de Cáncer
8 IBSLor - Ingénierie, Biologie et Santé en Lorraine
9 IJC - Josep Carreras Leukaemia Research Institute
10 IGTP - Institut d’Investigació Germans Trias i Pujol = Germans Trias i Pujol Research Institute
11 Biocruces Bizkaia Health Research Institute [Baracaldo]
12 CIBERehd - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
13 CNIO - Centro Nacional de Investigaciones Oncologicas / Spanish National Cancer Research Centre [Madrid, Espagne]
14 GTPUH - Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain]
15 IMoPA - Ingénierie Moléculaire et Physiopathologie Articulaire
16 JGU - Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University
17 UNITO - Università degli studi di Torino = University of Turin
18 NSHE - Nevada System of Higher Education
19 UPV / EHU - Universidad del País Vasco [Espainia] / Euskal Herriko Unibertsitatea [España] = University of the Basque Country [Spain] = Université du pays basque [Espagne]
Aitziber Ugalde-Olano
- Fonction : Auteur
Isabel Lacasa-Viscasillas
- Fonction : Auteur
Yuri Motorin
- Fonction : Auteur
- PersonId : 16579
- IdHAL : yuri-motorin
- ORCID : 0000-0002-8018-334X
- IdRef : 134883004
Mark Helm
- Fonction : Auteur
- PersonId : 761481
- ORCID : 0000-0002-0154-0928
- IdRef : 182558657
Arkaitz Carracedo
- Fonction : Auteur
Sandra Blanco
- Fonction : Auteur
Résumé
Abstract Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N 7 -methylguanosine (m 7 G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m 7 G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m 7 G tRNA methylation in cancer cell translation control and tumour biology.