YTHDF3 Induces the Translation of m6A-Enriched Gene Transcripts to Promote Breast Cancer Brain Metastasis

Chang, Guoqiang; Shi, Lei; Ye, Youqiong; Shi, Hailing; Zeng, Lizhi; Tiwary, Shweta; Huse, Jason T.; Huo, Lei; Ma, Li; Ma, Yihui; Zhang, Sicong; Zhu, Jianwei; Xie, Victoria K.; Li, Peng; Han, Leng; He, Chuan; Huang, Suyun

doi:10.1016/j.ccell.2020.10.004

Cited by 249 publications

(209 citation statements)

References 46 publications

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“…The most prominent finding to emerge from our data is that the difference in m 6 A modification between the tumor tissues and corresponding normal tissues was significant, which was also observed in breast cancer, non-small cell lung cancer, and pancreatic adenocarcinoma with different methylation levels [ 29 – 31 ]. This result suggests that the m 6 A modification could contribute to IMPA progression.…”

Section: Discussionsupporting

confidence: 55%

Comprehensive analysis of the transcriptome‐wide m6A methylome in invasive malignant pleomorphic adenoma

et al. 2021

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Background Invasive malignant pleomorphic adenoma (IMPA) is a highly invasive parotid gland tumor and lacks effective therapy. N6-Methyladenosine (m6A) is the most prevalent post-transcriptional modification of mRNAs in eukaryotes and plays an important role in the pathogenesis of multiple tumors. However, the significance of m6A-modified mRNAs in IMPA has not been elucidated to date. Hence, in this study, we attempted to profile the effect of IMPA in terms of m6A methylation in mRNA. Methods Methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were utilized to acquire the first transcriptome-wide profiling of the m6A methylome map in IMPA followed by bioinformatics analysis. Results In this study, we obtained m6A methylation maps of IMPA samples and normal adjacent tissues through MeRIP-seq. In total, 25,490 m6A peaks associated with 13,735 genes were detected in the IMPA group, whereas 33,930 m6A peaks associated with 18,063 genes were detected in the control group. Peaks were primarily enriched within coding regions and near stop codons with AAACC and GGAC motifs. Moreover, functional enrichment analysis demonstrated that m6A-containing genes were significantly enriched in cancer and metabolism relevant pathways. Furthermore, we identified a relationship between the m6A methylome and the RNA transcriptome, indicating a mechanism by which m6A modulates gene expression. Conclusions Our study is the first to provide comprehensive and transcriptome-wide profiles to determine the potential roles played by m6A methylation in IMPA. These results may open new avenues for in-depth research elucidating the m6A topology of IMPA and the molecular mechanisms governing the formation and progression of IMPA.

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Section: Discussionsupporting

confidence: 55%

Comprehensive analysis of the transcriptome‐wide m6A methylome in invasive malignant pleomorphic adenoma

et al. 2021

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“…Wen et al found that m6A on ncRNA NEAT1-1 plays a critical role in the pathogenesis and development of bone metastatic prostate cancer [ 8 ]. Chang et al demonstrated that overexpression of YTH domain-containing family protein 3 (YTHDF3) could induce the transcription of m6A-enriched genes to promote breast cancer metastasis [ 9 ]. In addition, Geng et al systematically analyzed the relation between m6A RNA methylation-related genes and the survival of pancreatic cancer [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Analysis of m6A RNA Methylation-Related Genes in Liver Hepatocellular Carcinoma and Their Correlation with Survival

Zhu

et al. 2021

IJMS

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N6-methyladenosine (m6A) modification on RNA plays an important role in tumorigenesis and metastasis, which could change gene expression and even function at multiple levels such as RNA splicing, stability, translocation, and translation. In this study, we aim to conduct a comprehensive analysis on m6A RNA methylation-related genes, including m6A RNA methylation regulators and m6A RNA methylation-modified genes, in liver hepatocellular carcinoma, and their relationship with survival and clinical features. Data, which consist of the expression of widely reported m6A RNA methylation-related genes in liver hepatocellular carcinoma from The Cancer Genome Atlas (TCGA), were analyzed by one-way ANOVA, Univariate Cox regression, a protein–protein interaction network, gene enrichment analysis, feature screening, a risk prognostic model, correlation analysis, and consensus clustering analysis. In total, 405 of the m6A RNA methylation-related genes were found based on one-way ANOVA. Among them, DNA topoisomerase 2-alpha (TOP2A), exodeoxyribonuclease 1 (EXO1), ser-ine/threonine-protein kinase Nek2 (NEK2), baculoviral IAP repeat-containing protein 5 (BIRC5), hyaluronan mediated motility receptor (HMMR), structural maintenance of chromosomes protein 4 (SMC4), bloom syndrome protein (BLM), ca-sein kinase I isoform epsilon (CSNK1E), cytoskeleton-associated protein 5 (CKAP5), and inner centromere protein (INCENP), which were m6A RNA methylation-modified genes, were recognized as the hub genes based on the protein–protein interaction analysis. The risk prognostic model showed that gender, AJCC stage, grade, T, and N were significantly different between the subgroup with the high and low risk groups. The AUC, the evaluation parameter of the prediction model which was built by RandomForest, was 0.7. Furthermore, two subgroups were divided by consensus clustering analysis, in which stage, grade, and T differed. We identified the important genes expressed significantly among two clusters, including uridine-cytidine kinase 2 (UCK2), filensin (BFSP1), tubulin-specific chaperone D (TBCD), histone-lysine N-methyltransferase PRDM16 (PRDM16), phosphorylase b ki-nase regulatory subunit alpha (PHKA2), serine/threonine-protein kinase BRSK2 (BRSK2), Arf-GAP with coiled-coil (ACAP3), general transcription factor 3C polypep-tide 2 (GTF3C2), and guanine nucleotide exchange factor MSS4 (RABIF). In our study, the m6A RNA methylation-related genes in liver hepatocellular carcinoma were analyzed systematically, including the expression, interaction, function, and prognostic values, which provided an important theoretical basis for m6A RNA methylation in liver cancer. The nine important m6A-related genes could be prognostic markers in the survival time of patients.

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“…Another study has proposed that overexpressed YTHDF1 and YTHDF3 promotes translation of oncogenes in a m6A-dependent manner in BC, resulting in tumor progression and inferior outcomes ( 51 ). YTHDF3 expression in BC brain metastases is higher than that in BC and nontumor tissues, and facilitates expressions of ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 5 (ST6GALNAC5), gap junction proteinα1 (GJA1), EGFR, and vascular endothelial growth factor A (VEGFA) in a m 6 A-dependent manner during the regulation of multiple steps in brain metastases ( 40 ).…”

Section: Function Of Yth Domain Family Proteins In Malignant Tumorsmentioning

confidence: 99%

“…With recent striking combination treatment effects of cancer-immunotherapy ( 40 , 47 ), identifying m 6 A-related immunotherapy-sensitive tumor types and understanding how m 6 A modifications influence immunotherapy sensitivity and radiosensitivity are urgently needed.…”

Section: Future Prospectsmentioning

confidence: 99%

YTH Domain Proteins: A Family of m6A Readers in Cancer Progression

Zhang

Shen

et al. 2021

Front. Oncol.

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N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs). m6A RNA methylation is involved in all stages of RNA life cycle, from RNA processing, nuclear output, translation regulation to RNA degradation, indicating that m6A has various functions affecting RNA metabolism positively or negatively. Reading proteins are vital in regulating the translation and stability of m6A mRNAs positively or negatively. Recent studies have enhanced the understanding of the molecular mechanism of the YT521-B homology (YTH) domain family and the modification of m6A. This study aimed to review the specific mechanisms, functions, and interactions of the YTH domain protein family. It also discussed future research directions, thus providing new ideas for the clinical diagnosis and targeted therapy of cancer.

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YTHDF3 Induces the Translation of m6A-Enriched Gene Transcripts to Promote Breast Cancer Brain Metastasis

Cited by 249 publications

References 46 publications

Comprehensive analysis of the transcriptome‐wide m6A methylome in invasive malignant pleomorphic adenoma

Comprehensive analysis of the transcriptome‐wide m6A methylome in invasive malignant pleomorphic adenoma

Analysis of m6A RNA Methylation-Related Genes in Liver Hepatocellular Carcinoma and Their Correlation with Survival

YTH Domain Proteins: A Family of m6A Readers in Cancer Progression

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