Mechanism of RNA modification N6-methyladenosine in human cancer

Zhou, Zijian; Lv, Jialun; Yu, Hao; Han, Jie; Yang, Xiao; Feng, Dexiang; Wu, Qikai; Yuan, Baorui; Lü, Qiang; Yang, Haiwei

doi:10.1186/s12943-020-01216-3

Cited by 207 publications

(198 citation statements)

References 159 publications

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“…The abnormal expression of m6A “writer” proteins results in abnormal levels of m6A modification in tumor cells, which further abnormalizes the metabolism of tumor-related genes mRNA, thereby promoting the development of a variety of cancers ( 8 , 9 ). The up-regulated METTL3 in gastric cancer was positively correlated with the poor prognosis of patients, and METTL3 promoted epithelial–mesenchymal transition of gastric cancer, leading to tumor invasion and metastasis ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer

et al. 2020

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ObjectivesRecently, an increasing number of studies have revealed that N6-methyladenosine (m6A) functions as a significant post-transcriptional modification which plays a critical role in the occurrence and progression of enriched tumors by regulating coding and non-coding RNA biogenesis. However, the biological function of m6A in breast cancer remains largely unclear.Materials and MethodsIn this study, we used a series of bioinformatic databases and tools to jointly analyze the expression of m6A methylation transferases (METTL3, METTL14, WTAP, RBM15, RBM15B and ZC3H13) and investigate the prognostic value of METTL14 and ZC3H13 in breast cancer. Besides, we analyzed the downstream carcinogenic molecular mechanisms related to METTL14 and ZC3H13 and their relationship with immune infiltration in breast tumor tissues.ResultsThe results showed that METTL14 and ZC3H13 were the down-regulated m6A methylation transferases in breast cancer. Survival outcome analysis suggested that abnormally low expression of METTL14 and ZC3H13 could predict unfavorable prognosis in four breast cancer subtypes. Moreover, their down-regulation was associated with ER-, PR- and triple-negative breast cancer patients, as well as tumor progression (increased Scarff, Bloom and Richardson grade status and Nottingham Prognostic Index classification). Co-expression analysis revealed that METTL14 and ZC3H13 had a strong positive correlation with APC, an antagonist of the Wnt signaling pathway, indicating they might cooperate in regulating proliferation, invasion, and metastasis of tumor cells. METTL14, ZC3H13, and APC expression levels had significant positive correlation with infiltrating levels of CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, and negative correlation with Treg cells in breast cancer.ConclusionsThis study demonstrated that down-regulation of METTL14 and ZC3H13 which act as two tumor suppressor genes was found in breast cancer and predicted poor prognosis. Their abnormal expression promoted breast cancer invasion by affecting pathways related to tumor progression and mediating immunosuppression.

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Section: Introductionmentioning

confidence: 99%

Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer

et al. 2020

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“…Previous studies have shown that m 6 A modi cation is involved in many biological processes in mammals, including mRNA splicing, export, localization, translation, and stability [44]. Moreover, the m 6 A methylation of several associated proteins has been closely related to tumorigenesis in a broad range of cancer types [45]. As a "writer" in the m 6 A methyltransferase complex, METTL3 has been shown to affect various biological behaviors and, in turn, mediate carcinogenesis and development.…”

Section: Discussionmentioning

confidence: 99%

METTL3-Mediated m6A mRNA Modification of FBXW7 Suppresses Lung Adenocarcinoma

Chang

Zhang

et al. 2020

Preprint

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BackgroundFBXW7 m6A modification plays an important role in lung adenocarcinoma (LUAD) progression; however, the underlying mechanisms remain unclear.MethodsThe correlation between FBXW7 and various genes related to m6A modification was analyzed using The Cancer Genome Atlas database. The regulatory effects of METTL3 on FBXW7 mRNA m6A modification were examined in a cell model, and the underlying mechanism was determined by methylated RNA immunoprecipitation, RNA immunoprecipitation, luciferase reporter, and mutagenesis assays. In vitro experiments were performed to further explore the biological effects of METTL3-mediated FBXW7 m6A modification on LUAD development.ResultsDecreased FBXW7 expression was accompanied by downregulated METTL3 expression in human LUAD tissues and was associated with a worse prognosis for LUAD in The Cancer Genome Atlas database. m6A was highly enriched in METTL3-mediated FBXW7 transcripts, and increased m6A modification in the coding sequence region increased its translation. Functionally, METTL3 overexpression or knockdown affected the apoptosis and proliferation phenotype of LUAD cells by regulating FBXW7 m6A modification and expression. Furthermore, FBXW7 overexpression in METTL3-depleted cells partially restored the suppression of LUAD cells in vitro and in vivo.ConclusionsOur findings reveal that METTL3 positively regulates FBXW7 expression and confirm the tumor-suppressive role of m6A-modiﬁed FBXW7, thus providing insight into its epigenetic regulatory mechanisms in LUAD initiation and development.

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“…As a result, a number of noncoding RNAs and their functional mechanisms have been identified and characterized in most types of cancer [ 3 , 4 ]. The modifications of genomic DNA and RNA also provide new insight into the functional mechanisms of nucleic acids in cancer [ 5 , 6 , 7 , 8 ]. Various DNA modifications regulate the expression of coding and noncoding genes beyond the traditional gene regulation mechanism through transcription factors [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Various DNA modifications regulate the expression of coding and noncoding genes beyond the traditional gene regulation mechanism through transcription factors [ 6 , 7 ]. Moreover, the RNA modifications modulate the functional activity of coding and noncoding RNAs [ 5 , 8 ]. Therefore, the scientific view of DNA and RNA as generators and by-products of proteins has been changing.…”

Section: Introductionmentioning

confidence: 99%