METTL1-mediated m7G modification of valine tRNAs drives metabolic adaptation in pancreatic ductal adenocarcinoma cells
Jiabei Zhu, Qi Zhang, Douglas Evans, Rui Su, Qiuhui Pan, Ajay Goel
Jiabei Zhu, Qi Zhang, Douglas Evans, Rui Su, Qiuhui Pan, Ajay Goel
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Research Article Gastroenterology Oncology

METTL1-mediated m7G modification of valine tRNAs drives metabolic adaptation in pancreatic ductal adenocarcinoma cells

Abstract

Transfer RNA (tRNA) modifications play a critical role in regulating codon-specific mRNA translation and enabling tumor cell adaptation. The RNA methyltransferase 1 (METTL1) installs N7-methylguanosine (m7G) modifications on tRNAs, thereby shaping codon usage and translational output. However, the function and mechanistic contribution of the METTL1/tRNA axis in pancreatic ductal adenocarcinoma (PDAC) remain poorly defined. Here, we showed that METTL1 was overexpressed in PDAC tissues and that elevated METTL1 expression was associated with poor patient survival. Genetic ablation of METTL1 markedly suppressed PDAC cell proliferation, migration, and tumor growth in vitro and in vivo. Mechanistically, METTL1 loss selectively reduced m7G-modified valine tRNAs — particularly Val-AAC, Val-CAC, and Val-TAC — leading to impaired translation of valine-enriched OXPHOS transcripts. As a consequence, METTL1 deficiency disrupted mitochondrial respiration and energy production in PDAC cells. Consistent with this model, valine tRNA levels were elevated in PDAC tissues, and their selective depletion phenocopied METTL1 loss by impairing mitochondrial bioenergetics and tumor cell fitness. Thus, the METTL1/valine tRNA axis promoted PDAC progression through codon-dependent translational control of the mitochondrial electron transport chain and oxidative metabolism. Together, our findings identify a METTL1/tRNA/mitochondria signaling axis as a metabolic vulnerability and a promising therapeutic target in pancreatic cancer.

Authors

Jiabei Zhu, Qi Zhang, Douglas Evans, Rui Su, Qiuhui Pan, Ajay Goel

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Figure 1

METTL1 is elevated in PDAC and correlates with a poor prognosis.

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METTL1 is elevated in PDAC and correlates with a poor prognosis. (A) Alt...
(A) Alteration of METTL1 in human cancers from TCGA (CBioPortal). (B and C) Relative mRNA expression of METTL1 (B) and WDR4 (C) in pancreatic cancer and normal pancreatic tissues from TCGA and the GTEx databases. ***P < 0.001, by 2-tailed, unpaired t test. (D) Kaplan-Meier disease-free survival (DFS) analysis of PDAC patients with low or high METTL1 expression from TCGA database. Patients were divided into high and low expression groups using the median expression value as the cutoff. P = 0.0398, by log-rank (Mantel-Cox) test. (E) Kaplan-Meier DFS analysis of PDAC patients with low or high expression of WDR4 from TCGA database. Patients were divided into high and low expression groups using the median expression value as the cutoff. P = 0.0256, by log-rank (Mantel-Cox) test. (F and G) Relative mRNA expression levels of METTL1 (F) and WDR4 (G) were evaluated by qRT-PCR in a cohort of 40 paired PDAC and AN tissue specimens. ***P < 0.001, by 2-tailed, paired t test. (H) Western blot analysis of METTL1 protein expression in 10 paired PDAC and AN tissue samples and quantification of relative METTL1 protein levels normalized to α-tubulin. ***P < 0.001, by 2-tailed, paired t test. (I) Representative IHC images showing endogenous METTL1 and WDR4 expression in PDAC and normal pancreatic tissues from The Human Protein Atlas database, with corresponding H scores quantified and presented as bar graphs. Scale bar: 100 μm; original magnification, ×20; insets ×71. ***P < 0.001, by 2-tailed, unpaired t test. Data are representative of 3 independent experiments. All data are presented as the mean ± SD.