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M6A methyltransferase METTL3 suppresses colorectal cancer proliferation and migration through p38/ERK pathways.

ABSTRACT: Purpose: Although many biological processes are involved in the modification of N6-methyladenosine (m6A), the exact role of m6A in the development of malignant tumors remains unclear. Methyltransferase 3 (METTL3) is a major RNA N6-methyladenosine methyltransferase. We aimed to explore the role of METTL3 in colorectal cancer (CRC) carcinogenesis and disease progression. Methods: In this study, immunohistochemistry was performed with a tissue microarray. qRT-PCR and Western blots were used to evaluate the expression of METTL3 in CRC cells. The effect of METTL3 on cell proliferation, migration and invasion of CRC cells was examined by IncuCyte Live Cell Analysis System and transwell assay, respectively. Results: The results suggested that positive expression of METTL3 was significantly associated with longer survival time (P=0.011). We next demonstrated that overexpression of METTL3 could inhibit proliferation, migration and invasion in CRC cells, while downregulation of METTL3 shows the opposite result. Furthermore, downregulation of METTL3 resulted in activation of p-p38 and p-ERK. Moreover, the inhibitors of p38 or ERK kinase could significantly reverse the effect of migration and invasion, which was induced by knockdown of METTL3. Conclusion: We concluded that METTL3 played a tumor-suppressive role in CRC cell proliferation, migration and invasion through p38/ERK pathways, which indicated that METTL3 might be a novel marker for CRC carcinogenesis, progression and survival.

SUBMITTER: Deng R

PROVIDER: S-EPMC6556107 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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m6A methyltransferase METTL3 suppresses colorectal cancer proliferation and migration through p38/ERK pathways.

Deng Ru R Cheng Yikan Y Ye Shubiao S Zhang Jianwei J Huang Runqing R Li Peisi P Liu Huashan H Deng Qiling Q Wu Xianrui X Lan Ping P Deng Yanhong Y

OncoTargets and therapy 20190604

Purpose: Although many biological processes are involved in the modification of N6-methyladenosine (m6A), the exact role of m6A in the development of malignant tumors remains unclear. Methyltransferase 3 (METTL3) is a major RNA N6-methyladenosine methyltransferase. We aimed to explore the role of METTL3 in colorectal cancer (CRC) carcinogenesis and disease progression. Methods: In this study, immunohistochemistry was performed with a tiss ...[more]

PMID: 31239708

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Project description:BackgroundNasopharyngeal carcinoma (NPC) is a malignancy of the head and neck that is prevalent in Southeast Asia and southern China. Recent studies in epigenetics suggest that DNA methylation plays a pivotal role in the onset and progression of cancer. Combining the methyl-DNA binding domain capture technique and cDNA microarray analysis, we identified a unique hypermethylated gene, RERG (Ras-like estrogen-regulated growth inhibitor), that was down-regulated in NPC tissues. RERG is a tumor suppressor gene that was first reported in breast cancer. However, the functions of RERG are largely unknown in other tumor types.MethodsRERG expression was assessed in human subjects (NPC primary tissues and non-cancer tissues) and cell lines (NPC cell lines and an immortalized epithelial cell line NP460). Further, we investigated the methylation rate of RERG in both human subject and cell lines. 5-Aza-2'-deoxycytidine (Aza) or combined with trichostatin A (TSA) were treated to three NPC cell lines (HK1, C666-1 and HK1_EBV). In addition, the role of RERG in NPC cells and its underlying mechanisms were explored by overexpression of RERG in NPC cell lines.ResultsRERG was significantly down-regulated in NPC cancer nests compared to normal nasopharyngeal epithelium cells. Furthermore, the RERG promoter was frequently methylated in NPC tissues and cell lines. The RERG methylation rate yielded an area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.897 (95%CI: 0.818-0.976). The down-regulation of RERG was restored in NPC cells treated with Aza and TSA. In addition, ectopic expression of RERG in NPC cell lines resulted in a significant suppression of cell proliferation, clonogenicity, migration and invasion. RERG-overexpressing cells showed significantly slower growth and less angiogenesis in tumor xenografts in nude mice. RERG suppressed the ERK/NF-κB signaling pathway and inhibited tumor growth and angiogenesis with down-regulation of MMPs and IL8 in tumors of nude mouse xenografts.ConclusionsOur results suggest that RERG is frequently silenced by promoter CpG methylation in NPC, and acts as a functional tumor suppressor by suppressing the ERK/NF-κB signaling pathway. These findings support the potential use of RERG as a novel molecular target in NPC therapy.

Dataset Information

M6A methyltransferase METTL3 suppresses colorectal cancer proliferation and migration through p38/ERK pathways.

Publications

m<sup>6</sup>A methyltransferase METTL3 suppresses colorectal cancer proliferation and migration through p38/ERK pathways.

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