Background:Cancer cells selectively promote the translation of oncogenic tran-scripts to stimulate cancer progression.Although growing evidence has revealed that tRNA modifications and related genes participate in thi...Background:Cancer cells selectively promote the translation of oncogenic tran-scripts 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 unchar-acterized.Here,we sought to investigate the function and mechanisms of the transfer RNA(tRNA)N7-methylguanosine(m'G)modification in regulating the occurrence and development of HNSCC.Methods:Cell lost of-function and gain-of function assays,xenograft models,conditional knockout and knockin mouse models were used to study the physi-ological functions of tRNA m'G modification in HNSCC tumorigenesis.tRNA modification and expression profiling,mRNA translation profiling and res-cue assays were performed to uncover the underlying molecular mechanisms.Single-cell RNA sequencing(scRNA seq)was conducted to explore the tumor microenvironment changes.Results:The tRNA.m7G 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'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 Mettll in mouse HNSCC.Furthermore,scRNA-seq results revealed that Mettll knockout in mouse tumor cells altered the immune landscape and cell-cell interaction between the tumor and stromal compartment.Conclusions:The tRNA m?G methyltransferase METTLI 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.METTLI could be a promising treatment target for HNSCC patients.展开更多
基金National Natural Science Foundation of China,Grant/Award Numbers:81872409,82173362Natural Science Foundation of Guangdong Province,Grant/Award Numbers:2018A030313610,2019A1515110110,2020A1515010291+1 种基金The Open Funding of the State Key Laboratory of Oral Diseases,Grant/Award Number:SKLOD2021OF02and the use was approved by the Institutional Review Board of the First Affiliated Hospital of Sun Yat-Sen University(2016074).The nude mouse experi-ments performed were approved by the Laboratory Ani-mal Center of Sun Yat-SenUniversity(SYSU-IACUC-2021-000092).The transgenic mouse experiments performed were approved by the Laboratory Animal Center of Sun Yat-Sen University(SYSU-IACUC-2020-000569).
文摘Background:Cancer cells selectively promote the translation of oncogenic tran-scripts 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 unchar-acterized.Here,we sought to investigate the function and mechanisms of the transfer RNA(tRNA)N7-methylguanosine(m'G)modification in regulating the occurrence and development of HNSCC.Methods:Cell lost of-function and gain-of function assays,xenograft models,conditional knockout and knockin mouse models were used to study the physi-ological functions of tRNA m'G modification in HNSCC tumorigenesis.tRNA modification and expression profiling,mRNA translation profiling and res-cue assays were performed to uncover the underlying molecular mechanisms.Single-cell RNA sequencing(scRNA seq)was conducted to explore the tumor microenvironment changes.Results:The tRNA.m7G 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'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 Mettll in mouse HNSCC.Furthermore,scRNA-seq results revealed that Mettll knockout in mouse tumor cells altered the immune landscape and cell-cell interaction between the tumor and stromal compartment.Conclusions:The tRNA m?G methyltransferase METTLI 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.METTLI could be a promising treatment target for HNSCC patients.
