Comprehensive characterization of m6A methylation and its impact on prognosis, genome instability, and tumor microenvironment in hepatocellular carcinoma

Yin, Tao; Zhao, Lang; Yao, Shukun

doi:10.1186/s12920-022-01207-x

Cited by 10 publications

(18 citation statements)

References 42 publications

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“…RNA m 6 A methylation has recently been shown to regulate tumor progression through effects on GI [ 255 ]. Yin et al [ 256 ] reported that multiple m 6 A regulators (METTL3, WTAP, YTHDF1/2/3) are associated with GI and mediate poor prognosis in HCC. Interestingly, METTL3-catalyzed m 6 A methylation is reported to mediate downregulation of the HMBOX1 gene, resulting in telomere dysfunction and inactivation of p53 signaling, thereby affecting telomere homeostasis and genome stability and promoting tumorigenesis [ 257 ].…”

Section: A Methylation Regulates the Biological Functions Of Tumor Cellsmentioning

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: A Methylation Regulates the Biological Functions Of Tumor Cellsmentioning

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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“…In addition, YTHDF3 contributed to hepatocarcinogenesis of mice induced by chemical carcinogens. At the same time, an analysis of the expression pattern of m 6 A regulator from Cancer Genome Atlas and Gene Expression Omnibus Database also shows that the expression of YTHDF3 is significantly increased in HCC tissues compared with normal tissues, and the high expression of YTHDF3 is closely related to the poor prognosis of HCC patients [ 13 ]. Moreover, highly-expressed lysine-specific demethylase 5B can promote proliferation, migration, invasion and other malignant phenotypes of HCC cells through miR-448 /YTHDF3/ITGA6 (Integrin subunit alpha 6) axis in hepatocellular carcinoma, confirming that YTHDF3 plays an important role in the occurrence and development of HCC [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

A functional loop between YTH domain family protein YTHDF3 mediated m6A modification and phosphofructokinase PFKL in glycolysis of hepatocellular carcinoma

Zhou

Qin

et al. 2022

J Exp Clin Cancer Res

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Background & aims N6-methyladenosine (m6A) modification plays a critical role in progression of hepatocellular carcinoma (HCC), and aerobic glycolysis is a hallmark of cancer including HCC. However, the role of YTHDF3, one member of the core readers of the m6A pathway, in aerobic glycolysis and progression of HCC is still unclear. Methods Expression levels of YTHDF3 in carcinoma and surrounding tissues of HCC patients were evaluated by immunohistochemistry. Loss and gain-of-function experiments in vitro and in vivo were used to assess the effects of YTHDF3 on HCC cell proliferation, migration and invasion. The role of YTHDF3 in hepatocarcinogenesis was observed in a chemically induced HCC model with Ythdf3−/− mice. Untargeted metabolomics and glucose metabolism phenotype assays were performed to evaluate relationship between YTHDF3 and glucose metabolism. The effect of YTHDF3 on PFKL was assessed by methylated RNA immunoprecipitation assays (MeRIP). Co-immunoprecipitation and immunofluorescence assays were performed to investigate the connection between YTHDF3 and PFKL. Results We found YTHDF3 expression was greatly upregulated in carcinoma tissues and it was correlated with poor prognosis of HCC patients. Gain-of-function and loss-of-function assays demonstrated YTHDF3 promoted proliferation, migration and invasion of HCC cells in vitro, and YTHDF3 knockdown inhibited xenograft tumor growth and lung metastasis of HCC cells in vivo. YTHDF3 knockout significantly suppressed hepatocarcinogenesis in chemically induced mice model. Mechanistically, YTHDF3 promoted aerobic glycolysis by promoting phosphofructokinase PFKL expression at both mRNA and protein levels. MeRIP assays showed YTHDF3 suppressed PFKL mRNA degradation via m6A modification. Surprisingly, PFKL positively regulated YTHDF3 protein expression, not as a glycolysis rate-limited enzyme, and PFKL knockdown effectively rescued the effects of YTHDF3 overexpression on proliferation, migration and invasion ability of Sk-Hep-1 and HepG2 cells. Notably, co-immunoprecipitation assays demonstrated PFKL interacted with YTHDF3 via EFTUD2, a core subunit of spliceosome involved in pre-mRNA splicing process, and ubiquitination assays showed PFKL could positively regulate YTHDF3 protein expression via inhibiting ubiquitination of YTHDF3 protein by EFTUD2. Conclusions our study uncovers the key role of YTHDF3 in HCC, characterizes a positive functional loop between YTHDF3 and phosphofructokinase PFKL in glucose metabolism of HCC, and suggests the connection between pre-mRNA splicing process and m6A modification.

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“…Further, research has shown that m6A modifiers are correlated with AML; for example, Huang et al found that fat mass and obesity-associated protein (FTO) is a mRNA m6A demethylase that can be targeted by small molecule inhibitors and has the potential to treat AML ( 12 ). Methyltransferase-like 14 ( METTL14 ) modulates its mRNA target through m6A modification to exert its carcinogenic effect, and METTL14 and m6A modification have key roles in normal and malignant hematopoiesis ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, very few studies have examined the relationship between the m6A-related signatures and TIME. There is also a study that enhances the understanding of the heterogeneity and complexity of TIME through a comprehensive analysis of specific m6A modulators to guide related immunotherapy ( 14 ). Unfortunately, these studies did not extend to AML.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of m6A-related signatures associated with the tumor immune microenvironment and predict survival in acute myeloid leukemia

Yuan¹,

Cong²,

Ji³

et al. 2022

Ann Transl Med

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Background Most previous studies have focused on the intrinsic carcinogenic pathways of tumors; however, little is known about the potential role of N6-methyladenosine (m6A) methylation in the tumor immune microenvironment (TIME). To better diagnose and treat acute myeloid leukemia (AML), we sought to examine the correlation between m6A regulatory factors and immune infiltration in cases of AML. At the same time, a prognostic model was constructed to predict the survival of AML. Methods We extracted data from The Cancer Genome Atlas (TCGA) database, including ribonucleic acid sequencing (RNA-seq) transcriptome data and data on the corresponding clinical characteristics of AML patients. We identified two m6A modification patterns with distinct clinical outcomes and found a significant relationship between them. Simultaneous discovery of distinct m6A clusters associated with the tumor immune microenvironment [immune cell types and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm] are closely related. Next, we implemented Lasso (Least Absolute Shrinkage and Selection Operator) Cox regression to build a predictive model in the 2-m6A regulator TCGA dataset to further explore m6A prognostic features in AML, and perform correlation validation. Results We identified 2 molecular subtypes (Clusters 1 and 2) by the consistent clustering of significant m6A regulators in AML. Cluster 2 was associated with a higher immune score and obvious immune cell infiltration, and thus patients in Cluster 2 had a poorer prognosis than those in Cluster 1 (P<0.05). Additionally, the 2 m6A-related signatures representing the independent prognostic factors in AML were screened to construct a prognostic risk-score model. We found that patients with low-risk scores had higher immune scores than those with high-risk scores (P<0.05). Conclusions Our research confirmed that m6A methylation plays an important role in AML. Further provide new directions for the prognosis and treatment of AML.

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Comprehensive characterization of m6A methylation and its impact on prognosis, genome instability, and tumor microenvironment in hepatocellular carcinoma

Cited by 10 publications

References 42 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

A functional loop between YTH domain family protein YTHDF3 mediated m6A modification and phosphofructokinase PFKL in glycolysis of hepatocellular carcinoma

Analysis of m6A-related signatures associated with the tumor immune microenvironment and predict survival in acute myeloid leukemia

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