Dataset Information

METTL1 promotes hepatocarcinogenesis via m⁷ G tRNA modification-dependent translation control.

ABSTRACT:

Background

N⁷ -methylguanosine (m⁷ G) modification is one of the most common transfer RNA (tRNA) modifications in humans. The precise function and molecular mechanism of m⁷ G tRNA modification in hepatocellular carcinoma (HCC) remain poorly understood.

Methods

The prognostic value and expression level of m⁷ G tRNA methyltransferase complex components methyltransferase-like protein-1 (METTL1) and WD repeat domain 4 (WDR4) in HCC were evaluated using clinical samples and TCGA data. The biological functions and mechanisms of m⁷ G tRNA modification in HCC progression were studied in vitro and in vivo using cell culture, xenograft model, knockin and knockout mouse models. The m⁷ G reduction and cleavage sequencing (TRAC-seq), polysome profiling and polyribosome-associated mRNA sequencing methods were used to study the levels of m⁷ G tRNA modification, tRNA expression and mRNA translation efficiency.

Results

The levels of METTL1 and WDR4 are elevated in HCC and associated with advanced tumour stages and poor patient survival. Functionally, silencing METTL1 or WDR4 inhibits HCC cell proliferation, migration and invasion, while forced expression of wild-type METTL1 but not its catalytic dead mutant promotes HCC progression. Knockdown of METTL1 reduces m⁷ G tRNA modification and decreases m⁷ G-modified tRNA expression in HCC cells. Mechanistically, METTL1-mediated tRNA m⁷ G modification promotes the translation of target mRNAs with higher frequencies of m⁷ G-related codons. Furthermore, in vivo studies with Mettl1 knockin and conditional knockout mice reveal the essential physiological function of Mettl1 in hepatocarcinogenesis using hydrodynamics transfection HCC model.

Conclusions

Our work reveals new insights into the role of the misregulated tRNA modifications in liver cancer and provides molecular basis for HCC diagnosis and treatment.

SUBMITTER: Chen Z

PROVIDER: S-EPMC8666584 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTranslation dysregulation plays a crucial role in tumourigenesis and cancer progression. Oncogenic translation relies on the stability and availability of tRNAs for protein synthesis, making them potential targets for cancer therapy.MethodsThis study performed immunohistochemistry analysis to assess NSUN2 levels in thyroid cancer. Furthermore, to elucidate the impact of NSUN2 on anaplastic thyroid cancer (ATC) malignancy, phenotypic assays were conducted. Drug inhibition and time-dependent plots were employed to analyse drug resistance. Liquid chromatography-mass spectrometry and bisulphite sequencing were used to investigate the m5 C methylation of tRNA at both global and single-base levels. Puromycin intake and high-frequency codon reporter assays verified the protein translation level. By combining mRNA and ribosome profiling, a series of downstream proteins and codon usage bias were identified. The acquired data were further validated by tRNA sequencing.ResultsThis study observed that the tRNA m5 C methyltransferase NSUN2 was up-regulated in ATC and is associated with dedifferentiation. Furthermore, NSUN2 knockdown repressed ATC formation, proliferation, invasion and migration both in vivo and in vitro. Moreover, NSUN2 repression enhanced the sensitivity of ATC to genotoxic drugs. Mechanically, NSUN2 catalyses tRNA structure-related m5 C modification, stabilising tRNA that maintains homeostasis and rapidly transports amino acids, particularly leucine. This stable tRNA has a substantially increased efficiency necessary to support a pro-cancer translation program including c-Myc, BCL2, RAB31, JUNB and TRAF2. Additionally, the NSUN2-mediated variations in m5C levels and different tRNA Leu iso-decoder families, partially contribute to a codon-dependent translation bias. Surprisingly, targeting NSUN2 disrupted the c-Myc to NSUN2 cycle in ATC.ConclusionsThis research revealed that a pro-tumour m5C methyltransferase, dynamic tRNA stability regulation and downstream oncogenes, c-Myc, elicits a codon-dependent oncogenic translation network that enhances ATC growth and formation. Furthermore, it provides new opportunities for targeting translation reprogramming in cancer cells.

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METTL1 promotes hepatocarcinogenesis via m⁷ G tRNA modification-dependent translation control.

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METTL1 promotes hepatocarcinogenesis via m⁷ G tRNA modification-dependent translation control.