The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells

Taketo,Kosuke; Konno,Masamitsu; Asai,Ayumu; Koseki,Jun; Toratani,Masayasu; Satoh,Taroh; Doki,Yuichiro; Mori,Masaki; Ishii,Hideshi; Ogawa,Kazuhiko

doi:10.3892/ijo.2017.4219

The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells

Authors:
- Kosuke Taketo
- Masamitsu Konno
- Ayumu Asai
- Jun Koseki
- Masayasu Toratani
- Taroh Satoh
- Yuichiro Doki
- Masaki Mori
- Hideshi Ishii
- Kazuhiko Ogawa
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Affiliations: Department of Radiation Oncology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan, Department of Medical Data Science, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan, Department of Cancer Frontier Science, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Published online on: December 7, 2017 https://doi.org/10.3892/ijo.2017.4219
Pages: 621-629

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Abstract

N6-methyladenosine (m6A) is the most abundant epitranscriptome modification in mammalian mRNA. Recent years have seen substantial progress in m6A epitranscriptomics, indicating its crucial roles in the initiation and progression of cancer through regulation of RNA stabilities, mRNA splicing, microRNA processing and mRNA translation. However, by what means m6A is dynamically regulated or written by enzymatic components represented by methyltransferase-like 3 (METTL3) and how m6A is significant for each of the numerous genes remain unclear. We focused on METTL3 in pancreatic cancer, the prognosis of which is not satisfactory despite the development of multidisciplinary therapies. We established METTL3-knockdown pancreatic cancer cell line using short hairpin RNA. Although morphologic and proliferative changes were unaffected, METTL3-depleted cells showed higher sensitivity to anticancer reagents such as gemcitabine, 5-fluorouracil, cisplatin and irradiation. Our data suggest that METTL3 is a potent target for enhancing therapeutic efficacy in patients with pancreatic cancer. In addition, we performed cDNA expression analysis followed by gene ontology and protein-protein interaction analysis using the Database for Annotation, Visualization, and Integrated Discovery and Search Tool for the Retrieval of Interacting Genes/Proteins databases, respectively. The results demonstrate that METTL3 was associated with mitogen-activated protein kinase cascades, ubiquitin-dependent process and RNA splicing and regulation of cellular process, suggesting functional roles and targets of METTL3.

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