The m6A methyltransferase METTL3 regulates autophagy and sensitivity to cisplatin by targeting ATG5 in seminoma

Chen, Hanfei; Xiang, Yuan; Yin, Yinghao; Peng, Jingxuan; Peng, Dongyi; Li, Dongjie; Kitazawa, Riko; Tang, Yuxin; Yang, Jianfu

doi:10.21037/tau-20-1411

Cited by 26 publications

(27 citation statements)

References 37 publications

(46 reference statements)

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“…Given the holistic nature of TME, combining these strategies with m 6 A methylation-targeted therapy may be a future research direction for the development of effective antitumor agents. For instance, METTL3 silencing can be synergistically implemented with the glycolysis inhibitor 2-deoxyglucose (2-DG) to block HCC growth [ 298 ] and combined inhibition of METTL3 and autophagy increases the sensitivity of spermatocytoma to cisplatin [ 299 ]. Additionally, co-inhibition of YTHDF2, ATF4-induced autophagy, and glutamine provides a novel strategy for targeted therapy in colorectal cancer [ 300 ].…”

Section: Potential Clinical Applications Of M 6 a ...mentioning

confidence: 99%

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

et al. 2022

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The tumor microenvironment (TME), which is regulated by intrinsic oncogenic mechanisms and epigenetic modifications, has become a research hotspot in recent years. Characteristic features of TME include hypoxia, metabolic dysregulation, and immunosuppression. One of the most common RNA modifications, N6-methyladenosine (m6A) methylation, is widely involved in the regulation of physiological and pathological processes, including tumor development. Compelling evidence indicates that m6A methylation regulates transcription and protein expression through shearing, export, translation, and processing, thereby participating in the dynamic evolution of TME. Specifically, m6A methylation-mediated adaptation to hypoxia, metabolic dysregulation, and phenotypic shift of immune cells synergistically promote the formation of an immunosuppressive TME that supports tumor proliferation and metastasis. In this review, we have focused on the involvement of m6A methylation in the dynamic evolution of tumor-adaptive TME and described the detailed mechanisms linking m6A methylation to change in tumor cell biological functions. In view of the collective data, we advocate treating TME as a complete ecosystem in which components crosstalk with each other to synergistically achieve tumor adaptive changes. Finally, we describe the potential utility of m6A methylation-targeted therapies and tumor immunotherapy in clinical applications and the challenges faced, with the aim of advancing m6A methylation research.

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Section: Potential Clinical Applications Of M 6 a ...mentioning

confidence: 99%

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

et al. 2022

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“…It has been proved that m6A modi cation involved in the occurrence and development of tumor drug resistance [17]. We have detected m6A modi cation of total RNA in TCam-2 cell line and TCam-2/CDDP cell line, and the results showed that the m6A modi cation in total RNA of TCam-2/CDDP cells was signi cantly higher than that of TCam-2 cells [13]. Then, siRNA or plasmid was used for knockdown (si-METTL3) or overexpression (OE-METTL3) of METTL3 in TCam-2/CDDP cells, respectively.…”

Section: Mettl3 Can Enhance the Anti-apoptosis Ability Of Tcam-2/cddp Cellsmentioning

confidence: 78%

“…Researchers have suggested that m6A modi cation can induce the occurrence of anti-apoptosis in cancers by regulating the expression of classical anti-apoptosis genes [19][20]. In our previous study, we have proved that METTL3 confers resistance to cisplatin in TCam-2 cells [13]. Thus, we speculated that METTL3 could regulate the anti-apoptosis related genes through m6A modi cation and thus induce chemoresistance.…”

Section: Mettl3 Involves In Regulation Of Bcl2 In Tcam-2/cddp Cellsmentioning

confidence: 85%

“…M6A has a critical regulatory role in tumor stem cells and drug resistance [1], [12]. Our previous study found that METTL3 mediates cisplatin resistance through autophagy and modi ed TFAP2C [13][14] Platinum resistance can also result from defects in initiation of apoptosis,yet the classical anti-apoptosis gene BCL2 have not been proven to be determinants for chemoresistance in germ cell tumors [15][16][17]. Therefore, this study intends to explore the role of METTL3 in promoting the resistance of TCam-2 cells via classical anti-apoptosis gene BCL2.…”

Section: Introductionmentioning

confidence: 99%

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The m6A Methyltransferase METTL3 Promotes Cisplatin Resistance and Invasion in Testicular Seminoma via BCL2

Peng

Xiang

Lian

et al. 2021

Preprint

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Background: Methyltransferase-like 3 (METTL3) involves in promoting tumor progression through tumor-related genes N6-methyladenosine (m6A) modification. Our previous study found that METTL3 plays an important role in seminoma chemosensitivity. BCL-2 is a key cause of cisplatin resistance in many tumors. Therefore, we want to explore whether METTL3 affects cisplatin resistance of seminoma by regulating BCL-2.Methods: In this study, we downregulated and overexpressed METTL3 in TCam-2 cisplatin resistant cells (TCam-2/CDDP). Then, m6A RNA methylation quantification of BCL-2 and cell viability assay, cell apoptosis analysis and cell invasion assay were investigated under the condition of with or without cis‐dichlorodiammine platinum (CDDP) treatment. Results: Consistent with our previous results, METTL3 significantly affects the chemosensitivity of TCam-2/CDDP. After METTL3 downregulated, the proliferation and anti-apoptosis ability of TCam-2/CDDP cells significantly weakened. Correspondingly, overexpression of METTL3 could promote the chemoresistance. However, the phenotype could be partly reversed by decreasing the expression of BCL-2. Moreover, we found that the m6A modification of BCL-2 is more abundant in cisplatin-resistant strains. Knockdown and overexpression of METTL3 significantly affected the m6A modification and the protein level of BCL-2 in TCam-2/CDDP. Finally, we found that METTL3 also promoted the invasion ability of TCam-2/CDDP cells via BCL2.Conclusion: This study revealed that METTL3 promotes anti-apoptosis and invasion of TCam-2/CDDP through BCL-2. And it indicated that METTL3 and BCL-2 may be an effective treatment target for CDDP-resistance seminoma.

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“…FTO is identified to increase the expression of ATG5 and ATG7, and promote the autophagosome formation to promote both autophagy and adipogenesis ( Jin et al, 2018 ; Wang et al, 2020a ). In addition, the overexpression of METTL3 is proved to increase the level of m 6 A modification of ATG5 while the knockdown of ATG5 reduces the autophagy induced by METTL3, indicating that ATG5 is a key target to induce autophagy ( Chen et al, 2021 ). YTHDF1 promotes the translation of the ATG gene by combining with m 6 A-modified ATG2 and ATG14 mRNA, thereby promoting autophagy in human hepatocellular carcinoma ( Li et al, 2021 ).…”

Section: The Role Of M 6 a In Pcdmentioning

confidence: 99%

m6A: An Emerging Role in Programmed Cell Death

Tang

Chen

et al. 2022

Front. Cell Dev. Biol.

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Programmed cell death is an active extinction process, including autophagy, ferroptosis, pyroptosis, apoptosis, and necroptosis. m6A is a reversible RNA modification which undergoes methylation under the action of methylases (writers), and is demethylated under the action of demethylases (erasers). The RNA base site at which m6A is modified is recognized by specialized enzymes (readers) which regulate downstream RNA translation, decay, and stability. m6A affects many aspects of mRNA metabolism, and also plays an important role in promoting the maturation of miRNA, the translation and degradation of circRNA, and the stability of lncRNA. The regulatory factors including writers, erasers and readers promote or inhibit programmed cell death via up-regulating or down-regulating downstream targets in a m6A-dependent manner to participate in the process of disease. In this review, we summarize the functions of m6A with particular reference to its role in programmed cell death.

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The m6A methyltransferase METTL3 regulates autophagy and sensitivity to cisplatin by targeting ATG5 in seminoma

Cited by 26 publications

References 37 publications

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

The m6A Methyltransferase METTL3 Promotes Cisplatin Resistance and Invasion in Testicular Seminoma via BCL2

m6A: An Emerging Role in Programmed Cell Death

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