TY - JOUR
T1 - METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer
AU - García-Vílchez, Raquel
AU - Añazco-Guenkova, Ana M.
AU - Dietmann, Sabine
AU - López, Judith
AU - Morón-Calvente, Virginia
AU - D’Ambrosi, Silvia
AU - Nombela, Paz
AU - Zamacola, Kepa
AU - Mendizabal, Isabel
AU - García-Longarte, Saioa
AU - Zabala-Letona, Amaia
AU - Astobiza, Ianire
AU - Fernández, Sonia
AU - Paniagua, Alejandro
AU - Miguel-López, Borja
AU - Marchand, Virginie
AU - Alonso-López, Diego
AU - Merkel, Angelika
AU - García-Tuñón, Ignacio
AU - Ugalde-Olano, Aitziber
AU - Loizaga-Iriarte, Ana
AU - Lacasa-Viscasillas, Isabel
AU - Unda, Miguel
AU - Azkargorta, Mikel
AU - Elortza, Félix
AU - Bárcena, Laura
AU - Gonzalez-Lopez, Monika
AU - Aransay, Ana M.
AU - Di Domenico, Tomás
AU - Sánchez-Martín, Manuel A.
AU - De Las Rivas, Javier
AU - Guil, Sònia
AU - Motorin, Yuri
AU - Helm, Mark
AU - Pandolfi, Pier Paolo
AU - Carracedo, Arkaitz
AU - Blanco, Sandra
N1 - Publisher Copyright:
© The Author(s) 2023.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - 7-methylguanosine
KW - Epitranscriptome
KW - Immune checkpoint blockade
KW - Interferon
KW - Prostate cancer
KW - RNA modifications
KW - Tumour microenvironment (TME)
KW - tRNA fragments
UR - http://www.scopus.com/inward/record.url?scp=85165971512&partnerID=8YFLogxK
U2 - 10.1186/s12943-023-01809-8
DO - 10.1186/s12943-023-01809-8
M3 - Article
C2 - 37516825
AN - SCOPUS:85165971512
SN - 1476-4598
VL - 22
JO - Molecular Cancer
JF - Molecular Cancer
IS - 1
M1 - 119
ER -