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Pharmacological inhibition of METTL1 as a therapy against solid and haematological cancers [mim-tRNA-Seq]

ABSTRACT: The N7-methylguanosine (m7G) modification is one of the most prevalent modifications on tRNA, mainly catalysed by the METTL1-WDR4 protein complex. The m7G methyltranferase METTL1 has been connected to oncogenic transformation and maintenance of several aggressive malignancies but the impact of a therapeutic targeting a tRNA-modifying enzyme is yet to be determined. Here, we present the development and characterisation of STM9005, a highly selective and potent first-in-class tRNA methyltransferase inhibitor of METTL1. Treatment of numerous tumour models with STM9005 reduces cancer growth, causes cellular changes and dysregulates cell cycle progression. These cellular effects were accompanied by a selective decrease of m7G on a subset of tRNAs and a reduction in their expression levels, which led to an impact on oncogenic mRNA translation. We illustrate that pharmacological inhibition of METTL1 in vivo impairs tumour growth and leads to a significant prolongation of survival in various mouse cancer models of different tissue origin. Collectively, our results provide strong proof-of-concept that targeting of tRNA methylation is a novel avenue of anti-cancer therapy, and illustrate that catalytic inhibition of METTL1 represents a novel therapeutic strategy against a number of aggressive malignancies.

ORGANISM(S): Mus musculus

PROVIDER: GSE302571 | GEO | 2026/08/12

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE302571_B16F10_STM9005_3d_v_DMSO_3d_anticodon_count_table.csv.gz	Csv
	GSE302571_B16F10_STM9005_3d_v_DMSO_3d_mismatch_table.csv.gz	Csv
	GSE302571_MLLAF9_STM9005_3d_v_DMSO_3d_anticodon_count_table.csv.gz	Csv
	GSE302571_MLLAF9_STM9005_3d_v_DMSO_3d_mismatch_table.csv.gz	Csv

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Pharmacological inhibition of METTL1 as a therapy against solid and haematological cancers [RNA-Seq]

Project description:The N7-methylguanosine (m7G) modification is one of the most prevalent modifications on tRNA, mainly catalysed by the METTL1-WDR4 protein complex. The m7G methyltranferase METTL1 has been connected to oncogenic transformation and maintenance of several aggressive malignancies but the impact of a therapeutic targeting a tRNA-modifying enzyme is yet to be determined. Here, we present the development and characterisation of STM9005, a highly selective and potent first-in-class tRNA methyltransferase inhibitor of METTL1. Treatment of numerous tumour models with STM9005 reduces cancer growth, causes cellular changes and dysregulates cell cycle progression. These cellular effects were accompanied by a selective decrease of m7G on a subset of tRNAs and a reduction in their expression levels, which led to an impact on oncogenic mRNA translation. We illustrate that pharmacological inhibition of METTL1 in vivo impairs tumour growth and leads to a significant prolongation of survival in various mouse cancer models of different tissue origin. Collectively, our results provide strong proof-of-concept that targeting of tRNA methylation is a novel avenue of anti-cancer therapy, and illustrate that catalytic inhibition of METTL1 represents a novel therapeutic strategy against a number of aggressive malignancies.

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Project description:Transfer RNAs (tRNAs) are exceptionally subject to modifications, including methylation. While mRNA methylation is emerging as an important regulator of biological and pathological processes in cancer, how post-transcriptional methylation of tRNAs contributes to cancer is largely unknown. Here we show that the RNA N7-methylguanosine (m7G) methyltransferase METTL1 is highly differentially expressed in prostate cancer compared to non-tumour prostate tissues. METTL1 expression regulation is mediated under the oncogenic PI3K-PTEN pathway. Knockdown of METTL1 dramatically inhibits prostate cancer cell growth and tumour progression in vivo. In contrast, overexpression of the wild type but not the catalytically inactive METTL1 potentiates cell growth. Thus, METTL1-mediated methylation is important for prostate tumorigenesis. Mechanistically we find that METTL1 depletion causes loss of m7G tRNA methylation and increases endonucleolytic cleavage of tRNA leading to an accumulation of 5′ tRNA-derived small RNA fragments. 5′ tRNA-derived fragments steer translation control to favour synthesis of key regulators of tumour growth suppression and immune rejection. In summary, our findings uncover a critical function of m7G tRNA methylation in directing translation control in cancer cells with important implications for tumour growth and unveil METTL1 inhibition as a promising anti-cancer therapeutic strategy.

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