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

Raquel García-Vílchez, Ana M. Añazco-Guenkova, Sabine Dietmann, Judith López, Virginia Morón-Calvente, Silvia D'Ambrosi, Paz Nombela, Kepa Zamacola, Isabel Mendizabal, Saioa García-Longarte, Amaia Zabala-Letona, Ianire Astobiza, Sonia Fernández, Alejandro Paniagua, Borja Miguel-López, Virginie Marchand, Diego Alonso-López, Angelika Merkel, Ignacio García-Tuñón, Aitziber Ugalde-OlanoAna Loizaga-Iriarte, Isabel Lacasa-Viscasillas, Miguel Unda, Mikel Azkargorta, Félix Elortza, Laura Bárcena, Monika Gonzalez-Lopez, Ana M. Aransay, Tomás Di Domenico, Manuel A. Sánchez-Martín, Javier De Las Rivas, Sònia Guil, Yuri Motorin, Mark Helm, Pier Paolo Pandolfi, Arkaitz Carracedo, Sandra Blanco

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)119
Number of pages1
JournalMolecular Cancer
Volume22
Issue number1
DOIs
StatePublished - Jul 29 2023

Keywords

  • 7-methylguanosine
  • Epitranscriptome
  • Immune checkpoint blockade
  • Interferon
  • Prostate cancer
  • RNA modifications
  • Tumour microenvironment (TME)
  • tRNA fragments

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