METTL1 promotes hepatocarcinogenesis via m⁷G tRNA modification‐dependent translation control

Abstract

Background N 7 ‐methylguanosine (m 7 G) modification is one of the most common transfer RNA (tRNA) modifications in humans. The precise function and molecular mechanism of m 7 G tRNA modification in hepatocellular carcinoma (HCC) remain poorly understood. Methods The prognostic value and expression level of m 7 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 m 7 G tRNA modification in HCC progression were studied in vitro and in vivo using cell culture, xenograft model, knockin and knockout mouse models. The m 7 G reduction and cleavage sequencing (TRAC‐seq), polysome profiling and polyribosome‐associated mRNA sequencing methods were used to study the levels of m 7 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 m 7 G tRNA modification and decreases m 7 G‐modified tRNA expression in HCC cells. Mechanistically, METTL1‐mediated tRNA m 7 G modification promotes the translation of target mRNAs with higher frequencies of m 7 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.

N7-Methylguanosine-Related lncRNAs: Integrated Analysis Associated With Prognosis and Progression in Clear Cell Renal Cell Carcinoma

“…Besides, substantial evidence also revealed the connection between the aberrant m7G RNA modification and the development of a wide range of cancers such as prostate cancer, liver cancer, lung cancer, bladder cancer, etc. ( D’Abronzo et al, 2017 ; Chen et al, 2021 ; Ma J et al, 2021 ; Ying et al, 2021 )…”

The potential role of N7-methylguanosine (m7G) in cancer

“…WDR4 is also highly expressed and increases malignant phenotypes in multiple malignancies, including AML, ESCC, HCC, HNSCC, IC, LC, and NPC. Increased expression of WDR4 is regarded as an unfavorable prognostic biomarker in such cancers [ 24 , 43 , 52 , 59 , 66 , 68 , 78 ]. In addition, METTL1 expression is associated with extremely poor prognosis in KIRC and mesothelioma, while it is related to superior survival in patients with ovarian serous cystadenocarcinoma [ 56 ].…”

“…The m7G regulators perform different roles in different types of tumors. For example, METTL1 and WDR4 play a strong carcinogenic role in AML, BC, ESCC, glioma, HCC, HNSCC, ICC, LC, and NPC, promoting the malignant phenotype and progression of tumors [ 24 , 26 , 43 , 52 , 56 , 59 , 60 , 66 , 68 , 78 ]; however, METTL1 exerts a significant anti-cancer effect in CC [ 48 ]. WBCCR22 restrains PC development, while accelerating glioma progression [ 57 , 80 ].…”

“…Some evidence demonstrates that m7G methylation is closely associated with tumor development and is involved in multiple tumor-related biological activities [ 24 – 27 ]. In the present review, we concentrate on the cutting-edge progress made in the study of m7G modification with a particular focus on the functions of m7G in cancer development and progression, in addition to exploring the future directions of m7G research.…”

“…The oncogenic function of METTL1 in HCC has been reported to boost proliferation and migration by suppressing PTEN-related signaling pathways [ 60 ]. Another study validated the high protein expression levels of METTL1 and WDR4 in HCC tissues versus corresponding normal tissues and demonstrated that the inhibition of METTL1 or WDR4 globally decreases m7G tRNA modification and reduces HCC progression [ 24 ]. With respect to the mechanism, METTL1/WDR4 regulates the translation of cyclin A2 ( CCNA2 ), epidermal growth factor receptor ( EGFR ), and vascular endothelial growth factor A ( VEGFA ) mRNA in an m7G-modified tRNA-dependent manner.…”