METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer

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 N7-methylguanosine (m7G)...

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Detalles Bibliográficos
Autores: García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizabal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire|||0000-0002-7142-7066, Fernández, Sonia, Paniagua, Alejandro|||0000-0002-7794-8321, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika|||0000-0001-5164-6803, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Felix|||0000-0001-8839-5438, Barcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M.|||0000-0002-8271-612X, Di Domenico, Tomás, Sánchez-Martín, Manuel A.|||0000-0001-8370-1336, De Las Rivas, Javier, Guil, Sonia|||0000-0002-2257-3331, Motorin, Yuri, Helm, Mark|||0000-0002-0154-0928, Pandolfi, Pier Paolo, Carracedo, Arkaitz|||0000-0001-5957-1260, Blanco, Sandra
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:289901
Acceso en línea:https://ddd.uab.cat/record/289901
https://dx.doi.org/urn:doi:10.1186/s12943-023-01809-8
Access Level:acceso abierto
Palabra clave:Epitranscriptome
RNA modifcations
Prostate cancer
7-methylguanosine
Trna fragments
Tumour microenvironment (TME)
Interferon
Immune checkpoint blockade
Descripción
Sumario: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 N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G 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 m7G tRNA methylation in cancer cell translation control and tumour biology.

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