2. Academic Validation
  3. N7-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis

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

  • Nat Commun. 2022 Mar 18;13(1):1478. doi: 10.1038/s41467-022-29125-7.
Hui Han  # 1,  Chunlong Yang  # 1,  Jieyi Ma  # 1,  Shuishen Zhang  # 2,  Siyi Zheng  # 1,  Rongsong Ling 3,  Kaiyu Sun 4,  Siyao Guo 1,  Boxuan Huang 3,  Yu Liang 1,  Lu Wang 1,  Shuang Chen 1,  Zhaoyu Wang 1,  Wei Wei 1,  Ying Huang 5,  Hao Peng 1,  Yi-Zhou Jiang 3,  Junho Choe 6 7,  Shuibin Lin 8 9
Affiliations

Affiliations

  • 1 Department of Otolaryngology, Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 2 Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 3 Institute for Advanced Study, Shenzhen University, Shenzhen, 518057, China.
  • 4 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China.
  • 5 Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 6 Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, 04763, Republic of Korea.
  • 7 Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, Republic of Korea.
  • 8 Department of Otolaryngology, Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. [email protected].
  • 9 State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. [email protected].
  • # Contributed equally.
PMID: 35304469 DOI: 10.1038/s41467-022-29125-7
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.

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