Roles and drug development of METTL3 (methyltransferase-like 3) in anti-tumor therapy

Xu, Pengfei; Ge, Raoling

doi:10.1016/j.ejmech.2022.114118

Cited by 58 publications

(33 citation statements)

References 136 publications

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“…With the deepening of the RNA epitranscriptomic research studies, some m 6 A regulators have been selected as targets for the development of corresponding drugs, especially within the field of oncology. Nucleoside and non-nucleoside METTL3 inhibitors were designed to inhibit the function of METTL3 in different kinds of tumours and proved METTL3 was an efficient therapeutic target ( Xu and Ge, 2022 ). METTL14 also plays an important role in a variety of tumours.…”

Section: Discussionmentioning

confidence: 99%

The landscape of m1A modification and its posttranscriptional regulatory functions in primary neurons

Zhang

Hou

et al. 2023

eLife

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Cerebral ischaemia‒reperfusion injury (IRI), during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m1A) is an RNA modification that can affect gene expression and RNA stability. The m1A landscape and potential functions of m1A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m1A modification in normal and OGD/R-treated mouse neurons and the effect of m1A on diverse RNAs. We investigated the m1A landscape in primary neurons, identified m1A-modified RNAs, and found that OGD/R increased the number of m1A RNAs. m1A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA–RNA binding proteins (RBPs) interactions and circRNA translation. We showed that m1A modification mediates the circRNA/lncRNA‒miRNA–mRNA competing endogenous RNA (ceRNA) mechanism and that 3' untranslated region (3’UTR) modification of mRNAs can hinder miRNA–mRNA binding. Three modification patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m1A-regulatory specificity. Systematic analysis of the m1A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA modification and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology-related diseases.

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Section: Discussionmentioning

confidence: 99%

The landscape of m1A modification and its posttranscriptional regulatory functions in primary neurons

Zhang

Hou

et al. 2023

eLife

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“…Therefore, we hypothesize that FSCN1 forms an RBP regulatory network with multiple mRNAs, which is the molecular basis of the metastasis in various tumors. The m6A methyltransferase METTL3 epigenetically regulates the transcription and translation of critical genes involved in multiple biological pathways and disease including cancer [31][32][33]. Previous studies have shown that METTL3 regulates chemoresistance and immune escape of BLCA cells [34,35], we also explored the potential non-methyltransferase functions of METTL3 in BLCA.…”

Section: Discussionmentioning

confidence: 99%

FSCN1/METTL3/TLN1 axis promotes the malignant progression in bladder carcinoma

Sun

Liu

Wang

et al. 2022

Preprint

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Background The RNA-binding protein (RBP) played an important role in tumors. FSCN1 functioned as an oncogene in bladder carcinoma (BLCA). FSCN1 has not been reported as an RBP in BLCA. The mechanism by which FSCN1 promoted BLCA invasion and metastasis has remained unclear. Methods The FSCN1-bound RNAs in BLCA cell lines were identified using RIP-sequencing. The regulatory relationship between FSCN1 and METTL3 or TLN1 was verified by RNA immunoprecipitation (RIP), RNA pulldown assay, co-immunoprecipitation (Co-IP), western blotting, quantitative real-time PCR (qRT-PCR) and immunofluorescence. The metastatic abilities of the BCLA cells were evaluated by in vitro wound healing and transwell assays, as well as in vivo models. Results TLN1 protein levels were higher in BLCA tissues compared to the paired para-tumor tissues, whereas its mRNA expression was lower in the tumors. Mechanistically, FSCN1 bound to and upregulated METTL3, which in turn repressed TLN1 mRNA expression through the latter’s 3'UTR. In addition, FSCN1 bound to the CDS region of TLN1 mRNA and promoted its translation. Knocking down FSCN1, METTL3 and TLN1 individually had an inhibitory effect on the proliferation, invasion, migration and metastasis of BLCA cells. Conclusions FSCN1 functions as an RBP to promote proliferation, invasion and migration of BLCA cells. The FSCN1/METTL3/TLN1 axis is a potential therapeutic target for BLCA.

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“…As common RNA modi cations in eukaryotes, m 6 A has been considered to play key in epigenetic inheritance by participating in different bioprocesses [12] that affect COAD progression [13]. As a "writer" of m 6 A, METTL3 has been shown to affect tumours by in uencing ampli cation, metastasis, and treatment resistance [14]. Recent research has shown that METTL3, highly expressed in COAD, affects cell proliferation through CCNE1 [15]and SOX2[16], metastasis through mir-1246 [17], metabolism through HK2[18] and SLC2A1 [19], and immune response through STAT1 [20,21].…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine modification of RanGAP1 promotes colorectal cancer progression via CRABP2

Yang

Shi

et al. 2022

Preprint

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Ran GTPase activating protein 1 (RanGAP1) plays an important role in a variety of diseases; however, whether it affects colorectal cancer progression(COAD) is unclear. In this study, RanGAP1 was identified as a novel downstream gene of METTL3 in COAD by m6A epitranscriptomic microarray, MeRIP-seq and label-free proteomics analyses. RIP-qPCR and Luciferase reporter explored the molecular mechanism of m6A modifition. RNA-seq and label-free proteomics determined CRABP2 is a downstream target of RanGAP1. In vitro/vivo experiment verified the function upon RanGAP1 and CRABP2 silencing/overexpressing. The results showed RanGAP1 was highly expressed in COAD and CRABP2 was found to be positively correlated with RanGAP1. In addition, silencing RanGAP1/CRABP2 inhibited the tumorigenesis of COAD, while overexpressed RanGAP1 recused the influence of METTL3 sliencing in the malignant phenotype. Meanwhile, RanGAP1 affected the sensitivity of oxaliplatin and fluorouracil to COAD. Mechanistically, there is the direct interaction between METTL3/YTHDF1 and RanGAP1, and METTL3 mediates m6A methylation in the 3′UTR region of RanGAP1 mRNA and affects mRNA stability by recruiting YTHDF1. These results revealed RanGAP1 was a new downstream mechanism of METTL3-mediated m6A modification and promote COAD progression via CRABP2, which maybe is a potential therapeutic target for COAD.

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Roles and drug development of METTL3 (methyltransferase-like 3) in anti-tumor therapy

Cited by 58 publications

References 136 publications

The landscape of m1A modification and its posttranscriptional regulatory functions in primary neurons

The landscape of m1A modification and its posttranscriptional regulatory functions in primary neurons

FSCN1/METTL3/TLN1 axis promotes the malignant progression in bladder carcinoma

N6-methyladenosine modification of RanGAP1 promotes colorectal cancer progression via CRABP2

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