HNRNPC impedes m6A-dependent anti-metastatic alternative splicing events in pancreatic ductal adenocarcinoma

Huang, Xi‐Tai; Li, Jianhui; Zhu, Xiao-Xu; Huang, Chen‐Song; Gao, Zhuoxing; Xu, Qiong‐Cong; Zhao, Wei

doi:10.1016/j.canlet.2021.07.016

Cited by 56 publications

(42 citation statements)

References 21 publications

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“…Among a variety of m 6 A readers, YTHDC1, hnRNP A2B1, hnRNP C, and IGF2BP3 have been reported to regulate RNA splicing. 13 , 26 – 28 In order to investigate which m 6 A reader regulates the alternative splicing of RBM4, we conducted RT-PCR screening and found that only YTHDC1 knockdown can inhibit RBM4 exon inclusion (Supplementary Fig. S 6b ).…”

Section: Resultsmentioning

confidence: 99%

Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4

et al. 2022

Sig Transduct Target Ther

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Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression, yet how this process is regulated by oncogenic signal remains largely unknown. Here, we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m6A reader YTHDC1 in lung cancer. Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing, specifically triggering RBM4 splicing from the full isoform (RBM4-FL) to the short isoform (RBM4-S) in a kinase-independent manner. RBM4-S functions as a tumor promoter by abolishing RBM4-FL-mediated inhibition of the activity of the SRSF1-mTORC1 signaling pathway. Mechanistically, AURKA disrupts the binding of SRSF3 to YTHDC1, resulting in the inhibition of RBM4-FL production induced by the m6A-YTHDC1-SRSF3 complex. In turn, AURKA recruits hnRNP K to YTHDC1, leading to an m6A-YTHDC1-hnRNP K-dependent exon skipping to produce RBM4-S. Importantly, the small molecules that block AURKA nuclear translocation, reverse the oncogenic splicing of RBM4 and significantly suppress lung tumor progression. Together, our study unveils a previously unappreciated role of nuclear AURKA in m6A reader YTHDC1-dependent oncogenic RNA splicing switch, providing a novel therapeutic route to target nuclear oncogenic events.

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Section: Resultsmentioning

confidence: 99%

Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4

et al. 2022

Sig Transduct Target Ther

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“…In addition, as an m6A regulator, hnRNP C gives rise to a malignant phenotype in pancreatic ductal adenocarcinoma (PDAC) cells by antagonizing TAF8L (antimetastatic isoform) and increasing TAF8S (prometastatic alternative splicing isoform). When an m6A mutation occurs in TAF8, the interaction between hnRNP C and the TAF8 transcript weakens, and TAF8S expression decreases [ 80 ]. This indicates that the interaction between hnRNP C and m6A mediates shearing events that affect PDAC.…”

Section: Role Of Hnrnp C Dysregulation In Cancersmentioning

confidence: 99%

An analysis of the role of HnRNP C dysregulation in cancers

Meng

Huang

et al. 2022

Biomark Res

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Heterogeneous nuclear ribonucleoproteins C (HnRNP C) is part of the hnRNP family of RNA-binding proteins. The relationship between hnRNP C and cancers has been extensively studied, and dysregulation of hnRNP C has been found in many cancers. According to existing public data, hnRNP C could promote the maturation of new heterogeneous nuclear RNAs (hnRNA s, also referred to as pre-mRNAs) into mRNAs and could stabilize mRNAs, controlling their translation. This paper reviews the regulation and dysregulation of hnRNP C in cancers. It interacts with some cancer genes and other biological molecules, such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and double-stranded RNAs (dsRNAs). Even directly binds to them. The effects of hnRNP C on biological processes such as alternative cleavage and polyadenylation (APA) and N6-methyladenosine (m6A) modification differ among cancers. Its main function is regulating stability and level of translation of cancer genes, and the hnRNP C is regarded as a candidate biomarker and might be valuable for prognosis evaluation.

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“…AS events are often observed in human cancer cells, and these events are regulated by m6A modulators. For instance, in pancreatic ductal adenocarcinoma, HNRNPC inhibits m6Adependent antimetastatic AS events (Huang et al, 2021). In the case where the CLK1/SRSF5 pathway is activated, aberrant exon skipping in the METTL14 and Cyclin-L2 genes are induced, triggering pancreatic ductal adenocarcinoma cell proliferation and metastasis while also modulating m6A methylation (Chen S. et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

N6-methyladenosine RNA methylation regulator-related alternative splicing gene signature as prognostic predictor and in immune microenvironment characterization of patients with low-grade glioma

et al. 2022

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Background: N6-methyladenosine (m6A) RNA methylation is an important epigenetic modification affecting alternative splicing (AS) patterns of genes to regulate gene expression. AS drives protein diversity and its imbalance may be an important factor in tumorigenesis. However, the clinical significance of m6A RNA methylation regulator-related AS in the tumor microenvironment has not been investigated in low-grade glioma (LGG).Methods: We used 12 m6A methylation modulatory genes (WTAP, FTO, HNRNPC, YTHDF2, YTHDF1, YTHDC2, ALKBH5, YTHDC1, ZC3H13, RBM15, METTL14, and METTL3) from The Cancer Genome Atlas (TCGA) database as well as the TCGA-LGG (n = 502) dataset of AS events and transcriptome data. These data were downloaded and subjected to machine learning, bioinformatics, and statistical analyses, including gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Univariate Cox, the Least Absolute Shrinkage and Selection Operator (LASSO), and multivariable Cox regression were used to develop prognostic characteristics. Prognostic values were validated using Kaplan-Maier survival analysis, proportional risk models, ROC curves, and nomograms. The ESTIMATE package, TIMER database, CIBERSORT method, and ssGSEA algorithm in the R package were utilized to explore the role of the immune microenvironment in LGG. Lastly, an AS-splicing factor (SF) regulatory network was examined in the case of considering the role of SFs in regulating AS events.Results: An aggregate of 3,272 m6A regulator-related AS events in patients with LGG were screened using six machine learning algorithms. We developed eight AS prognostic characteristics based on splice subtypes, which showed an excellent prognostic prediction performance. Furthermore, quantitative prognostic nomograms were developed and showed strong validity in prognostic prediction. In addition, prognostic signatures were substantially associated with tumor immune microenvironment diversity, ICB-related genes, and infiltration status of immune cell subtypes. Specifically, UGP2 has better promise as a prognostic factor for LGG. Finally, splicing regulatory networks revealed the potential functions of SFs.Conclusion: The present research offers a novel perspective on the role of AS in m6A methylation. We reveal that m6A methylation regulator-related AS events can mediate tumor progression through the immune-microenvironment, which could serve as a viable biological marker for clinical stratification of patients with LGG so as to optimize treatment regimens.

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HNRNPC impedes m6A-dependent anti-metastatic alternative splicing events in pancreatic ductal adenocarcinoma

Cited by 56 publications

References 21 publications

Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4

Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4

An analysis of the role of HnRNP C dysregulation in cancers

N6-methyladenosine RNA methylation regulator-related alternative splicing gene signature as prognostic predictor and in immune microenvironment characterization of patients with low-grade glioma

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