Methylation of microRNA-338-5p by EED promotes METTL3-mediated translation of oncogene CDCP1 in gastric cancer.

Abstract

Unmasking the complex regulatory pathways that mediate the malignant phenotypes of cancer cells can provide novel targets for therapies that could limit the recurrence and metastasis of gastric cancer (GC). Herein, we intended to clarify the role of embryonic ectoderm development protein (EED), microRNA-228-5p (miR-338-5p), methyltransferase like 3 (METTL3) and CUB domain containing protein 1 (CDCP1) in GC. Differentially expressed miRNAs and their target genes were extracted by in silico analysis. The studies revealed high expression of EED in GC tissues and cell lines and it high expression in GC patients was shown to be associated with poor prognosis. The chromatin immunoprecipitation assay identified that EED methylated miR-338-5p to inhibit its expression. EED knockdown could restrain the proliferative and invasive abilities of GC cells by inducing miR-338-5p. Furthermore, miR-338-5p targeted m6A methylase METTL3, while METTL3 amplified the translation of CDCP1 via m6A activity which led to accelerated proliferation and invasion of GC cells. Moreover, in vivo experiments validated that EED promoted the progression of GC through mediating the miR-338-5p/METTL3/CDCP1 axis. Collectively, EED downregulated miR-338-5p through histone methylation, which in turn impaired miR-338-5p-dependent METTL3 inhibition and enhanced CDCP1 translation, therefore contributing to the development of GC.

• Authors: Fangbin Zhang, Yan Yan, Xinguang Cao, Jinping Zhang, Yingxia Li, Changqing Guo
• Journal: Aging (Aging (Albany NY)) Vol. 13 Issue 8 Pg. 12224-12238 (04 21 2021) ISSN: 1945-4589 [Electronic] United States
• PMID: 33882457 (Publication Type: Journal Article)

Chemical References

• Antigens, Neoplasm
• CDCP1 protein, human
• Cell Adhesion Molecules
• EED protein, human
• MIRN338 microRNA, human
• MicroRNAs
• N-methyladenosine
• Methyltransferases
• Polycomb Repressive Complex 2
• METTL3 protein, human
• Adenosine

Topics

• Adenosine (analogs & derivatives, metabolism)
• Aged
• Animals
• Antigens, Neoplasm (biosynthesis)
• Cell Adhesion Molecules (biosynthesis)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Disease-Free Survival
• Female
• Follow-Up Studies
• Gastrectomy
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Male
• Methylation
• Methyltransferases (metabolism)
• Mice
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Neoplasm Recurrence, Local (epidemiology, genetics)
• Polycomb Repressive Complex 2 (genetics, metabolism)
• Prognosis
• Protein Biosynthesis (genetics)
• Stomach (pathology, surgery)
• Stomach Neoplasms (genetics, mortality, pathology, surgery)
• Xenograft Model Antitumor Assays