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

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

Fecha de publicación:

Autores de IBSAL

Autores ajenos a IBSAL

  • Dietmann, S
  • D'Ambrosi, S
  • Zamacola, K
  • Mendizabal, I
  • García-Longarte, S
  • Zabala-Letona, A
  • Astobiza, I
  • Fernández, S
  • Paniagua, A
  • Marchand, V
  • Merkel, A
  • Ugalde-Olano, A
  • Loizaga-Iriarte, A
  • Lacasa-Viscasillas, I
  • Unda, M
  • Azkargorta, M
  • Elortza, F
  • Bárcena, L
  • Gonzalez-Lopez, M
  • Aransay, AM
  • Di Domenico, T
  • Guil, S
  • Motorin, Y
  • Helm, M
  • Pandolfi, PP
  • Carracedo, A

Grupos

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.

Datos de la publicación

ISSN/ISSNe:
1476-4598, 1476-4598

Molecular Cancer  BIOMED CENTRAL LTD

Tipo:
Article
Páginas:
-

Citas Recibidas en Web of Science: 18

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Keywords

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

Campos de estudio

Financiación

AECC (LABAE19040BLAN)
AECC (RED2018-102769-T)
Castilla- Leon autonomous government
Consejeria de Educacion de la Junta de Castilla y Leon (PRDSA19002LOPE)
Cris contrael cancer (FPU19/01190)
CRUE-CSIC
ERDF Away of making Europe
ESF Investing in your future (GCTRA18006CARR)
European Regional Development Fund (CLC201701)
European Research Council (819242)
European Research Council (819242)
European Union (PID2019-111692RB-I00)
European Union (SAF2016-78667-R)
FEDER funds
ISCIII
Junta de Castilla y Leon - Fondo Social Europeo
La Caixa Foundation (100010434)
La Caixa Foundation (LCF/PR/HR17)
MICINN (PID2019-108787RB-I00)
MICINN (PR_TPD_2020-19)
MICINN/AEI
MINECO (RYC-2014-16550)
MIU (BES-2017-080530)
Programa de Apoyo a Planes Estrategicos de Investigacion de Estructuras de Investigacion de Excelencia
Proteored-ISCIII
Spanish Ministry of Science and Innovation MICINN/AEI
Springer Nature
USAL-Santander PhD fellowship

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