N6-methyladenosine demethyltransferase FTO-mediated autophagy in malignant development of oral squamous cell carcinoma

Wang, Fang; Liao, Yan; Zhang, Ming; Zhu, Yue; Wang, Wenjin; Cai, Hao; Liang, Jianfeng; Fan, Song; Hou, Chen; Huang, Shuojin; Zhang, Yadong; Wang, Cheng

doi:10.1038/s41388-021-01820-7

Cited by 58 publications

(59 citation statements)

References 65 publications

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“…METTL3 and METTL14 can regulate the progression of multiple types of cancer, including bladder cancer [ 15 , 16 ], gastric cancer [ 17 , 18 ], cervical cancer [ 19 ], hepatocellular carcinoma [ 14 , 20 ], and pancreatic cancer [ 21 ]. FTO plays a central role in oral squamous cell carcinoma [ 22 ], hepatocellular carcinoma [ 23 ], bladder cancer [ 24 ], and acute myeloid leukemia [ 9 , 25 ]. Although studies have also demonstrated that m6A modification plays a key role in CRC [ 4 , 12 ], the function and regulatory mechanism of m6A in CRC progression remain unclear.…”

Section: Introductionmentioning

confidence: 99%

METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

Pan

Liu

Xiao

et al. 2022

J Exp Clin Cancer Res

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Background Colorectal carcinoma (CRC) is the third most common cancer and second most common cause of cancer-related deaths worldwide. Ribonucleic acid (RNA) N6-methyladnosine (m6A) and methyltransferase-like 3 (METTL3) play key roles in cancer progression. However, the roles of m6A and METTL3 in CRC progression require further clarification. Methods Adenoma and CRC samples were examined to detect m6A and METTL3 levels, and tissue microarrays were performed to evaluate the association of m6A and METTL3 levels with the survival of patients with CRC. The biological functions of METTL3 were investigated through cell counting kit-8, wound healing, and transwell assays. M6A epitranscriptomic microarray, methylated RNA immunoprecipitation-qPCR, RNA stability, luciferase reporter, and RNA immunoprecipitation assays were performed to explore the mechanism of METTL3 in CRC progression. Results M6A and METTL3 levels were substantially elevated in CRC tissues, and patients with CRC with a high m6A or METTL3 levels exhibited shorter overall survival. METTL3 knockdown substantially inhibited the proliferation, migration, and invasion of CRC cells. An m6A epitranscriptomic microarray revealed that the cell polarity regulator Crumbs3 (CRB3) was the downstream target of METTL3. METTL3 knockdown substantially reduced the m6A level of CRB3, and inhibited the degradation of CRB3 mRNA to increase CRB3 expression. Luciferase reporter assays also showed that the transcriptional level of wild-type CRB3 significantly increased after METTL3 knockdown but not its level of variation. Knockdown of YT521-B homology domain–containing family protein 2 (YTHDF2) substantially increased CRB3 expression. RNA immunoprecipitation assays also verified the direct interaction between the YTHDF2 and CRB3 mRNA, and this direct interaction was impaired after METTL3 inhibition. In addition, CRB3 knockdown significantly promoted the proliferation, migration, and invasion of CRC cells. Mechanistically, METTL3 knockdown activated the Hippo pathway and reduced nuclear localization of Yes1-associated transcriptional regulator, and the effects were reversed by CRB3 knockdown. Conclusions M6A and METTL3 levels were substantially elevated in CRC tissues relative to normal tissues. Patients with CRC with high m6A or METTL3 levels exhibited shorter overall survival, and METTL3 promoted CRC progression. Mechanistically, METTL3 regulated the progression of CRC by regulating the m6A–CRB3–Hippo pathway.

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Section: Introductionmentioning

confidence: 99%

METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

Pan

Liu

Xiao

et al. 2022

J Exp Clin Cancer Res

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“…Eukaryotic translation initiation factor 4 gamma 1 (eIF4G1) is an important translation factor in eukaryotic organisms, promoting mitochondrial activity and cell proliferation while inhibiting autophagy ( 23 ). Through meRIP-seq and RNA-seq analysis ( 22 ), we found that eIF4G1 mRNA was downregulated and m 6 A level was upregulated in the rapamycin-induced autophagy cell model. We speculated that m 6 A triggers the degradation of eIF4G1 mRNA.…”

Section: Resultsmentioning

confidence: 99%

“…However, we obtained the opposite result in autophagyinhibited cells (treatment with 3MA) (Figure 1C), suggesting that METTL14 and FTO may act as key enzymes affecting m 6 A expression during autophagy activation. In a previous study, we demonstrated the inhibitory effect of FTO on autophagy (22). Therefore, the present study focused on the effect of METTL14 on autophagy.…”

Section: Autophagy Activation Promoted the Upregulation Of Mettl14 Expression In Oscc Cellsmentioning

confidence: 88%

“…Recent studies have shown that m 6 A affects malignant tumour progression by regulating the proliferation, differentiation, and apoptosis of tumour cells ( 17 – 21 ), but the relationship between m 6 A and autophagy is not entirely clear. In our previous studies, we have discovered the role of m 6 A demethylation by FTO in regulating autophagy ( 22 ). In this study, we further explored the specific molecular mechanism of m 6 A RNA methyltransferase METTL14 for regulating autophagy in OSCC.…”

Section: Introductionmentioning

confidence: 99%

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N6-Methyladenosine Methyltransferase METTL14-Mediated Autophagy in Malignant Development of Oral Squamous Cell Carcinoma

et al. 2021

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N6-methyladenosine (m6A) is the most abundant internal mRNA modification in eukaryotes and is related to stability, localization, or translation efficiency in tumorigenesis. Autophagy plays an important role in the occurrence and development of tumours. However, the relationship between m6A and autophagy remains unclear. In this study, we used a rapamycin-induced autophagy model of oral squamous cell carcinoma (OSCC) cells, and observed increased m6A RNA methylation. When autophagy was activated, the methyltransferase-like 14 (METTL14) expression was upregulated and influenced the proliferation, migration, and invasiveness of OSCC cells. Through meRIP-seq and RNA-seq analysis, we found that METTL14 directly combined with eukaryotic translation initiation factor gamma 1 (eIF4G1) mRNA and decreased its RNA stability. According to the dual-luciferase reporter and mutagenesis assay, the mutated site 1 of exon 11 of eIF4G1 is the key target of METTL14. Knockdown of the main m6A binding protein YTHDF2 may rescue the shortened half-life of eIF4G1 mRNA induced by METTL14 overexpression. Furthermore, an in vivo tumour xenograft model confirmed that a high METTL14 expression can effectively reduce OSCC growth. Additionally, using clinical samples, we found that patients with advanced or moderately/poorly differentiated tumours exhibited lower METTL14 levels. Taken together, our results revealed that METTL14 mediated eIF4G1 expression via m6A modification and regulated autophagy levels and biological functions in OSCC. Our findings not only expand our understanding of the correlation between autophagy and RNA methylation in tumorigenesis but also present an opportunity to develop new therapeutic options.

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“…Although previous studies have shown that the signature genes were related to a variety of cancers (liver cancer, breast cancer, oral cancer, and others), there have been few studies on the mechanism through which they participate in cancer progression (Li et al, 2017;Khowal et al, 2018;Uddin et al, 2018;Yao et al, 2019). Migration, proliferation, energy metabolism, and autophagy are all considered regulatory targets, but the underlying mechanism remains to be further elucidated (Hosgood et al, 2008;Wei et al, 2015;Jaiswal et al, 2018;Ma et al, 2020;Wang et al, 2021). In addition, HIF-1α, a key regulator of the tumour hypoxic response, may be implicated in the signature genes' association with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Significance of Parkinson Family Genes in the Prognosis and Treatment Outcome Prediction for Lung Adenocarcinoma

Xiao

Zhang

et al. 2021

Front. Mol. Biosci.

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Epidemiological investigations have shown that patients with Parkinson’s disease (PD) have a lower probability of developing lung cancer. Subsequent research revealed that PD and lung cancer share specific genetic alterations. Therefore, the utilisation of PD biomarkers and therapeutic targets may improve lung adenocarcinoma (LUAD) diagnosis and treatment. We aimed to identify a gene-based signature from 25 Parkinson family genes for LUAD prognosis and treatment choice. We analysed Parkinson family gene expression and protein levels in LUAD, utilising multiple databases. Least absolute shrinkage and selection operator (LASSO) regression was used to construct a prognostic model based on the TCGA-LUAD cohort. We validated the model in external GEO cohorts. Immune cell infiltration was compared between risk groups, and GEO data was used to explore the model’s predictive ability for LUAD treatment response. Nearly all Parkinson family genes exhibited significant differential expression between LUAD and normal tissues. LASSO regression confirmed that our seven Parkinson family gene-based signature had excellent prognostic performance for LUAD, as validated in three GEO cohorts. The high-risk group was clearly associated with low tumour immune cell infiltration, suggesting that immunotherapy may not be an optimal treatment choice. This is the first Parkinson family gene-based model for the prediction of LUAD prognosis and treatment outcome. The association of these genes with poor prognosis and low immune infiltration requires further investigation.

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N6-methyladenosine demethyltransferase FTO-mediated autophagy in malignant development of oral squamous cell carcinoma

Cited by 58 publications

References 65 publications

METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

N6-Methyladenosine Methyltransferase METTL14-Mediated Autophagy in Malignant Development of Oral Squamous Cell Carcinoma

Significance of Parkinson Family Genes in the Prognosis and Treatment Outcome Prediction for Lung Adenocarcinoma

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