METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer
Authors
García Vílchez , Raquel; Añazco Guenkova, Ana Macrina; Dietmann, Sabine; Lopez, Judith; Morón Calvente, Virginia; [et al.]Identifiers
Permanent link (URI): http://hdl.handle.net/10017/60488DOI: 10.1186/s12943-023-01809-8
ISSN: 1476-4598
Date
2023-07-29Bibliographic citation
Molecular Cancer, 2023, v. 22, n. 1, p. 1-36
Keywords
Epitranscriptome
RNA modifications
Prostate cancer
7-methylguanosinet
RNA fragments
Tumour microenvironment (TME)
InterferonImmune checkpoint blockade
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/publishedVersion
Rights
© The Authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Access rights
info:eu-repo/semantics/openAccess
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.
Files in this item
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MET_Garcia_MolCan_2023.pdf | 4.713Mb |
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MET_Garcia_MolCan_2023.pdf | 4.713Mb |
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