1. Academic Validation
  2. METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway

METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway

  • Cell Death Dis. 2023 Nov 25;14(11):765. doi: 10.1038/s41419-023-06287-w.
Yuechao Sun # 1 Weipeng Gong # 2 Song Zhang 3
Affiliations

Affiliations

  • 1 Ningbo Institute of Life and Health Industry, Chinese Academy of Sciences, Ningbo, Zhejiang, The People's Republic of China.
  • 2 Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, The People's Republic of China.
  • 3 Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University Affiliated Tumor Hospital, Jinan, Shandong, The People's Republic of China. qingchengguose@163.com.
  • # Contributed equally.
Abstract

The role of METTL3-mediated N6-methyladenosine (m6A) modification has been elucidated in several cancers, but the concrete mechanism underlying its function in colorectal Cancer is still obscure. Here, we revealed that upregulated methyltransferase-like 3 (METTL3) in colorectal Cancer exerted both methyltransferase activity-dependent and -independent functions in gene regulation. METTL3 deposited m6A on the 3' untranslated region of the JAK1 transcript to promote JAK1 translation relying on YTHDF1 recognition. Besides, METTL3 was redistributed to the STAT3 promoter and worked in concert with NF-κB to facilitate STAT3 transcription, which was achieved independently on METTL3 methyltransferase activity. The increased JAK1 and STAT3 corporately contributed to the activation of the p-STAT3 signaling pathway and further upregulated downstream effectors expressions, including VEGFA and CCND1, which finally resulted in enhanced Cancer cell proliferation and metastasis in vitro and in vivo. Collectively, our study revealed the unappreciated dual role of METTL3 as an m6A writer and a transcription regulator, which worked together in the same signaling pathway to drive colorectal Cancer malignancy.

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