METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumourigenesis

Wei, Xueju; Huo, Yue; Pi, Jingnan; Gao, Yufeng; S, Rao; He, Manman; Wei, Qinglv; Song, Peng; Chen, Yiying; Lü, Duo; Song, Wei; Liang, Junbo; Xu, lingjie; Wang, Haixia; Hong, Guolin; Guo, Yuehong; Si, Yanmin; Xu, Jiayue; Wang, Xiaoshuang; Ma, Yupo; Yu, Shuyang; Zou, Dongling; Jin, Jing; Wang, Fang; Yu, Jia

doi:10.1038/s41556-022-00968-y

Cited by 85 publications

(73 citation statements)

References 45 publications

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“…Recent studies showed that some known WERs of RNA modification have modification-independent functions. For instance, the m6A writer METTL3 could promote the translation of target gene PAPBC1 without m6A modification ( 66 ). The m6A writer METTL16 exerts an m6A-independent function to facilitate translation and tumorigenesis ( 67 ).…”

Section: Resultsmentioning

confidence: 99%

RM2Target: a comprehensive database for targets of writers, erasers and readers of RNA modifications

Bao

Zhang

et al. 2022

Nucleic Acids Research

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RNA modification is a dynamic and reversible process regulated by a series of writers, erasers and readers (WERs). Abnormal changes of WERs will disrupt the RNA modification homeostasis of their target genes, leading to the dysregulation of RNA metabolisms such as RNA stability and translation, and consequently to diseases such as cancer. A public repository hosting the regulatory relationships between WERs and their target genes will help in understanding the roles of RNA modifications in various physiological and pathological conditions. Previously, we developed a database named ‘m6A2Target’ to host targets of WERs in m6A, one of the most prevalent RNA modifications in eukaryotic cells. To host all RNA modification (RM)-related WER–target associations, we hereby present an updated database, named ‘RM2Target’ (http://rm2target.canceromics.org/). In this update, RM2Target encompasses 1 619 653 WER–target associations for nine RNA modifications in human and mouse, including m6A, m6Am, m5C, m5U, m1A, m7G, pseudouridine, 2′-O-Me and A-to-I. Extensive annotations of target genes are available in RM2Target, including but not limited to basic gene information, RNA modifications, RNA–RNA/RNA–protein interactions and related diseases. Altogether, we expect that RM2Target will facilitate further downstream functional and mechanistic studies in the field of RNA modification research.

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Section: Resultsmentioning

confidence: 99%

RM2Target: a comprehensive database for targets of writers, erasers and readers of RNA modifications

Bao

Zhang

et al. 2022

Nucleic Acids Research

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“…In the present study, AS events regulated by KIAA1429 occurring in these genes were greatly enriched in the positive regulation of fibroblast proliferation and the decomposition of cell components during apoptosis, which were closely related to tumor progression. Meanwhile, a recent study demonstrated that key RNA methyltransferase METTL3 could promote tumorigenesis by enhancing translation of epigenetic factors in the absence of m 6 A (34). We propose that…”

Section: Discussionmentioning

confidence: 81%

KIAA1429 regulates alternative splicing events of cancer-related genes in hepatocellular carcinoma

Liu

Li²,

Li³

et al. 2022

Front. Oncol.

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Hepatocellular carcinoma (HCC) remains one of the most fatal malignancies with high morbidity and mortality rates in the world, whose molecular pathogenesis is incompletely understood. As an RNA-binding protein participating in the processing and modification of RNA, KIAA1429 has been proved to be implicated in the pathogenesis of multiple cancers. However, how KIAA1429 functions in alternative splicing is not fully reported. In the current study, multi-omics sequencing data were used to analyze and decipher the molecular functions and the underlying mechanisms of KIAA1429 in HCC samples. RNA sequencing data (RNA-seq) analysis demonstrated that in HCCLM3 cells, alternative splicing (AS) profiles were mediated by KIAA1429. Regulated AS genes (RASGs) by KIAA1429 were enriched in cell cycle and apoptosis-associated pathways. Furthermore, by integrating the RNA immunoprecipitation and sequencing data (RIP-seq) of KIAA1429, we found that KIAA1429-bound transcripts were highly overlapping with RASGs, indicating that KIAA1429 could globally regulate the alternative splicing perhaps by binding to their transcripts in HCCLM3 cells. The overlapping RASGs were also clustered in cell cycle and apoptosis-associated pathways. In particular, we validated the regulated AS events of three genes using clinical specimens from HCC patients, including the exon 6 of BPTF gene and a marker gene of HCC. In summary, our results shed light on the regulatory functions of KIAA1429 in the splicing process of pre-mRNA and provide theoretical basis for the targeted therapy of HCC.

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“…One of the limitations of this study is that only a small number of clinical samples from CC patients were used. Moreover, as a previous study revealed that METTL3 relocates in cytoplasm and exerts an m 6 A-independent function to regulate cancer progression [ 62 ], further researches are needed to investigate the functional complexity of METTL3 both in cytoplasm and nucleus. Finally, with accumulating evidence for the functional diversity of m 6 A modification during cancer processes, exploring the therapeutic potential of targeting m 6 A regulators and their target RNAs may be beneficial for tumor therapy and provide novel approaches for designing more effective anti-tumor treatments.…”

Section: Discussionmentioning

confidence: 99%

RNA N6-methyladenosine modification mediates downregulation of NR4A1 to facilitate malignancy of cervical cancer

Jia

et al. 2022

Cell Biosci

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Background N6-methyladenosine is the most abundant eukaryotic mRNA modification and alters a wide range of cellular processes in cancer. Therefore, defining the molecular details are critical for understanding the regulatory mechanism of m6A modification. Results We found that METTL3, a core m6A methyltransferase component, is upregulated and functions as an oncogene in cervical cancer. Mechanistically, METTL3 induces the degradation of m6A-modified transcripts of NR4A1 though YTHDF2-DDX6 pathway. In addition, NR4A1 overexpression attenuates the malignant progression through recruiting the LSD1/HDAC1/CoREST transcriptional repression complex to AKT1 promoter. Conclusions Our findings reveal that m6A regulates cervical cancer cellular progression through manipulating NR4A1 pathway.

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METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumourigenesis

Cited by 85 publications

References 45 publications

RM2Target: a comprehensive database for targets of writers, erasers and readers of RNA modifications

RM2Target: a comprehensive database for targets of writers, erasers and readers of RNA modifications

KIAA1429 regulates alternative splicing events of cancer-related genes in hepatocellular carcinoma

RNA N6-methyladenosine modification mediates downregulation of NR4A1 to facilitate malignancy of cervical cancer

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