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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Bibliographic Details
Authors: García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, Blanco, Sandra
Format: article
Status:Published version
Publication Date:2023
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/347759
Online Access:http://hdl.handle.net/10261/347759
https://api.elsevier.com/content/abstract/scopus_id/85165971512
Access Level:Open access
Keyword:Epitranscriptome
RNA modifications
Prostate cancer
7-methylguanosine
tRNA fragments
Tumour microenvironment (TME)
Interferon
Immune checkpoint blockade
Description
Summary: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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