Chen et al. 2022 (PRJNA722238)

General Details

Title Aberrant translation regulation by METTL1/WDR4-mediated tRNA N7-methylguanosine modification drives HNSCC progression
Organism
Number of Samples 8
Release Date 2021/04/15 00:00
Sequencing Types
Protocol Details

Study Links

Repository Details

SRA SRP314965
ENA SRP314965
GEO
BioProject PRJNA722238

Publication

Title
Authors Chen J,Li K,Chen J,Wang X,Ling R,Cheng M,Chen Z,Chen F,He Q,Li S,Zhang C,Jiang Y,Chen Q,Wang A,Chen D
Journal Cancer communications (London, England)
Publication Date 2022 Mar
Abstract Cancer cells selectively promote the translation of oncogenic transcripts to stimulate cancer progression. Although growing evidence has revealed that tRNA modifications and related genes participate in this process, their roles in head and neck squamous cell carcinoma (HNSCC) remain largely uncharacterized. Here, we sought to investigate the function and mechanisms of the transfer RNA (tRNA) N7-methylguanosine (m 7 G) modification in regulating the occurrence and development of HNSCC. Cell lost-of-function and gain-of-function assays, xenograft models, conditional knockout and knockin mouse models were used to study the physiological functions of tRNA m 7 G modification in HNSCC tumorigenesis. tRNA modification and expression profiling, mRNA translation profiling and rescue assays were performed to uncover the underlying molecular mechanisms. Single-cell RNA sequencing (scRNA-seq) was conducted to explore the tumor microenvironment changes. The tRNA m 7 G methyltransferase complex components Methyltransferase-like 1 (METTL1)/WD repeat domain 4 (WDR4) were upregulated in HNSCC and associated with a poor prognosis. Functionally, METTL1/WDR4 promoted HNSCC progression and metastasis in cell-based and transgenic mouse models. Mechanistically, ablation of METTL1 reduced the m 7 G levels of 16 tRNAs, inhibiting the translation of a subset of oncogenic transcripts, including genes related to the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. In addition, chemical modulators of the PI3K/Akt/mTOR signaling pathway reversed the effects of Mettl1 in mouse HNSCC. Furthermore, scRNA-seq results revealed that Mettl1 knockout in mouse tumor cells altered the immune landscape and cell-cell interaction between the tumor and stromal compartment. The tRNA m 7 G methyltransferase METTL1 was found to promote the development and malignancy of HNSCC through regulating global mRNA translation, including the PI3K/AKT/mTOR signaling pathway, and found to alter immune landscape. METTL1 could be a promising treatment target for HNSCC patients. © 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.
PMC PMC8923133
PMID 35179319
DOI
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)
SRR14243824 PRJNA722238 Homo sapiens HNSCC cells
SRR14243825 PRJNA722238 Homo sapiens HNSCC cells
SRR14243826 PRJNA722238 Homo sapiens HNSCC cells
SRR14243830 PRJNA722238 Homo sapiens HNSCC cells
SRR14243831 PRJNA722238 Homo sapiens HNSCC cells
SRR14243832 PRJNA722238 Homo sapiens HNSCC cells
SRR14243834 PRJNA722238 Homo sapiens HNSCC cells Ribo-Seq chx_harr
SRR14243836 PRJNA722238 Homo sapiens HNSCC cells Ribo-Seq chx_harr
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)

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