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N-甲基鸟苷转移 RNA 修饰通过 RPTOR/ULK1/自噬轴促进食管鳞状细胞癌发生。

N-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis.

机构信息

Department of Otolaryngology, Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.

Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.

出版信息

Nat Commun. 2022 Mar 18;13(1):1478. doi: 10.1038/s41467-022-29125-7.

DOI:10.1038/s41467-022-29125-7
PMID:35304469
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8933395/
Abstract

Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA mG methyltransferase complex proteins METTL1 and WDR4 are significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. In addition, METTL1 and WDR4 promote ESCC progression via the tRNA mG methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of mG-modified tRNAs and reduces the translation of a subset of oncogenic transcripts enriched in RPTOR/ULK1/autophagy pathway. Furthermore, ESCC models using Mettl1 conditional knockout and knockin mice uncover the essential function of METTL1 in promoting ESCC tumorigenesis in vivo. Our study demonstrates the important oncogenic function of mis-regulated tRNA mG modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment.

摘要

RNA 修饰失调促进致癌 mRNA 的加工和翻译，从而促进癌症进展，但其分子机制尚不清楚。在这里，我们揭示了 tRNA mG 甲基转移酶复合物蛋白 METTL1 和 WDR4 在食管鳞状细胞癌 (ESCC) 组织中显著上调，并与 ESCC 预后不良相关。此外，METTL1 和 WDR4 通过体外和体内的 tRNA mG 甲基转移酶活性促进 ESCC 进展。在机制上，METTL1 或 WDR4 的敲低导致 mG 修饰的 tRNA 表达减少，并降低富含 RPTOR/ULK1/自噬途径的一组致癌转录本的翻译。此外，使用 Mettl1 条件性敲除和敲入小鼠的 ESCC 模型揭示了 METTL1 在体内促进 ESCC 肿瘤发生中的重要功能。我们的研究表明，tRNA mG 修饰失调在 ESCC 中具有重要的致癌功能，并表明靶向 METTL1 及其下游信号轴可能是 ESCC 治疗的有前途的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/1bbaaa3c39e3/41467_2022_29125_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/3f65bffcc7ae/41467_2022_29125_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/95c6c4237417/41467_2022_29125_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/15f33ab78f14/41467_2022_29125_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/edec5449ab21/41467_2022_29125_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/5eeaad009844/41467_2022_29125_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/9e6e0ec65a3b/41467_2022_29125_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/1bbaaa3c39e3/41467_2022_29125_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/3f65bffcc7ae/41467_2022_29125_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/95c6c4237417/41467_2022_29125_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/15f33ab78f14/41467_2022_29125_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/edec5449ab21/41467_2022_29125_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/5eeaad009844/41467_2022_29125_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/9e6e0ec65a3b/41467_2022_29125_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8525/8933395/1bbaaa3c39e3/41467_2022_29125_Fig7_HTML.jpg

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