N7-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis

Hui Han, Chunlong Yang, Jieyi Ma, Shuishen Zhang, Siyi Zheng, Rongsong Ling, Kaiyu Sun, Siyao Guo, Boxuan Huang, Yu Liang, Lu Wang, Shuang Chen, Zhaoyu Wang, Wei Wei, Ying Huang, Hao Peng, Yi-Zhou Jiang, Junho Choe and Shuibin Lin ()
Additional contact information
Hui Han: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
Chunlong Yang: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
Jieyi Ma: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
Shuishen Zhang: The First Affiliated Hospital, Sun Yat-sen University
Siyi Zheng: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
Rongsong Ling: Institute for Advanced Study, Shenzhen University
Kaiyu Sun: The First Affiliated Hospital of Sun Yat-sen University
Siyao Guo: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
Boxuan Huang: Institute for Advanced Study, Shenzhen University
Yu Liang: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
Lu Wang: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
Shuang Chen: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
Zhaoyu Wang: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
Wei Wei: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
Ying Huang: The First Affiliated Hospital, Sun Yat-sen University
Hao Peng: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
Yi-Zhou Jiang: Institute for Advanced Study, Shenzhen University
Junho Choe: College of Natural Sciences, Hanyang University
Shuibin Lin: Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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 m7G 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 m7G methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of m7G-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 m7G modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment.

Date: 2022
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DOI: 10.1038/s41467-022-29125-7

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