1. Academic Validation
  2. The M6A methyltransferase METTL3 regulates proliferation in esophageal squamous cell carcinoma

The M6A methyltransferase METTL3 regulates proliferation in esophageal squamous cell carcinoma

  • Biochem Biophys Res Commun. 2021 Nov 26;580:48-55. doi: 10.1016/j.bbrc.2021.05.048.
Jiang Zou 1 Xiaowu Zhong 2 Xi Zhou 2 Qiyue Xie 1 Zhao Zhao 1 Xiaolan Guo 3 Yixiang Duan 4
Affiliations

Affiliations

  • 1 Research Center of Analytical Instrumentation, Key Laboratory of Bio-resource and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, 610065, Sichuan, China.
  • 2 Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China.
  • 3 Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China. Electronic address: alan5200@hotmail.com.
  • 4 Research Center of Analytical Instrumentation, Key Laboratory of Bio-resource and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, 610065, Sichuan, China. Electronic address: yduan@scu.edu.cn.
Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal human cancers with a lower 5-year survival rate. N6-methyladenosine (m6A) methylation, an important epigenetic modification, has been reported to associate with physiological and pathological processes of cancers. However, its role in ESCC remains unclear. In this work, we found that the m6A levels were elevated in ESCC Cancer tissues and ESCC cells. The PPI network demonstrated that METTL3, METTL14, WTAP, RBM15, and KIAA1429 were all significantly associated with each other. Moreover, we found a significant upregulation of METTL3 mRNA and protein amounts in ESCC tissues. The METTL3 mRNA expression level of tissues had associations with ESCC differentiation extent and sex (p < 0.05). The METTL3 mRNA expression level of tissues, sensitivity for diagnosing ESCC was 75.00%, specificity was 72.06% and area under the ROC curve was 0.8030. Depletion of METTL3 markedly diminished m6A levels in human ESCC cell lines and METTL3 overexpression restored the reduction in m6A levels. These results suggested that METTL3 is the primary Enzyme that modulates m6A methylation and a critical regulatory factor in ESCC. Additionally, METTL3 knockdown significantly suppressed the ESCC cell proliferation, while METTL3 overexpression markedly promoted ESCC cell proliferation both in cell and animal models. These results demonstrated that METTL3 promotes ESCC development. Furthermore, METTL3 may modulate the cell cycle of ESCC cells through a p21-dependent pattern. METTL3-guided m6A modification may contribute to the progression of ESCC via the p21-axis. Our study is the first investigation to report that METTL3-mediated m6A methylation plays a crucial role in ESCC oncogenesis and highlights that METTL3 might be a potential biomarker and therapeutic target for ESCC patients.

Keywords

Esophageal squamous cell carcinoma; Methyltransferase-like 3; N6-methyladenosine (m6A).

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