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RNA N6-methyladenosine reader YTHDC1 is essential for TGF-beta-mediated metastasis of triple negative breast cancer [RNA-Seq]

ABSTRACT: RNA N6-methyladenosine (m6A) modification and its regulators fine tune gene expression and contribute to tumorigenesis. Here, we uncover the oncogenic role and mechanism of YTHDC1, an m6A reader positively correlated to poor prognosis in breast cancer patients. In a mammary fat pad mouse model, YTHDC1 significantly promoted lung metastasis of triple negative breast cancer (TNBC) cells. Using transcriptome-wide sequencing techniques, we found dysregulation of metastasis-related pathways following YTHDC1 depletion and demonstrated that YTHDC1 is critical for nuclear export of SMAD3 mRNA. YTHDC1 depletion desensitizes TNBC cells to TGF-β, resulting in impaired TGF-β-induced gene signature and inhibition on epithelial-mesenchymal transition (EMT) and cell migration/invasion, which could be at least partially restored by SMAD3 overexpression. Furthermore, we show that the ability of YTHDC1 to recognize m6A on SMAD3 RNA is important for its oncogenic role. Collectively, our study unravels YTHDC1 as vital for distant TNBC metastasis by promoting TGF-β-mediated EMT via SMAD3.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193153 | GEO | 2023/03/25

REPOSITORIES: GEO

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RNA N6-methyladenosine reader YTHDC1 is essential for TGF-beta-mediated metastasis of triple negative breast cancer [m6A-Seq]

Project description:RNA N6-methyladenosine (m6A) modification and its regulators fine tune gene expression and contribute to tumorigenesis. Here, we uncover the oncogenic role and mechanism of YTHDC1, an m6A reader positively correlated to poor prognosis in breast cancer patients. In a mammary fat pad mouse model, YTHDC1 significantly promoted lung metastasis of triple negative breast cancer (TNBC) cells. Using transcriptome-wide sequencing techniques, we found dysregulation of metastasis-related pathways following YTHDC1 depletion and demonstrated that YTHDC1 is critical for nuclear export of SMAD3 mRNA. YTHDC1 depletion desensitizes TNBC cells to TGF-β, resulting in impaired TGF-β-induced gene signature and inhibition on epithelial-mesenchymal transition (EMT) and cell migration/invasion, which could be at least partially restored by SMAD3 overexpression. Furthermore, we show that the ability of YTHDC1 to recognize m6A on SMAD3 RNA is important for its oncogenic role. Collectively, our study unravels YTHDC1 as vital for distant TNBC metastasis by promoting TGF-β-mediated EMT via SMAD3.

2023-03-25 | GSE193155 | GEO

RNA N6-methyladenosine reader YTHDC1 is essential for TGF-beta-mediated metastasis of triple negative breast cancer [RIP-Seq]

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Expression data from Control and Six1 expressing MCF7 cells

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Long noncoding RNA ELIT-1 acts as a Smad3 cofactor to facilitate TGF-β/Smad signaling and promote epithelial-mesenchymal transition

Project description:TGF-β is involved in various biological processes, including development, differentiation, growth regulation, and epithelial-mesenchymal transition (EMT). In TGF-β/Smad signaling, receptor-activated Smad complexes activate or repress their target gene promoters. Smad cofactors are a group of Smad-binding proteins that promote recruitment of Smad complexes to these promoters. Long noncoding RNAs (lncRNAs), that behave as Smad cofactors have thus far not been identified. Here, we characterize a novel lncRNA EMT-associated lncRNA induced by TGF-β-1(ELIT-1). ELIT-1 was induced by TGF-β-stimulation via the TGF-β/Smad pathway in TGF-β-responsive cell lines. ELIT-1-depletion abrogated TGF-β-mediated EMT progression and expression of TGF-β target genes including Snail, a transcription factor critical for EMT. A positive correlation between high expression of ELIT-1 and poor prognosis in lung adenocarcinoma and gastric cancer patients suggests that ELIT-1 may be useful as a prognostic and therapeutic target. RIP assays revealed that ELIT-1 bound to Smad3, but not Smad2. In conjunction with Smad3, ELIT-1 enhanced Smad-responsive promoter activities by recruiting Smad3 to the promoters of its target genes including Snail, other TGF-β-target genes, and ELIT-1 itself. Collectively, these data show that ELIT-1 is a novel trans-acting lncRNA that forms a positive feedback loop to enhance TGF-β/Smad3 signaling and promote EMT progression.

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Long noncoding RNA ELIT-1 acts as a Smad3 cofactor to facilitate TGF-β/Smad signaling and promote epithelial-mesenchymal transition

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KAT6A acetylation of SMAD3 regulates tumor metastasis in triple-negative breast cancer

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2021-11-03 | GSE171230 | GEO

Structural basis of YTH domain as m6A reader

Project description:The N6-methyladenosine (m6A) is the most abundant internal modification in almost all eukaryotic messenger RNAs, and is dynamically regulated. Therefore, identification of m6A readers is especially important in determining the cellular function of m6A. YTHDF2 has recently been characterized as the first m6A reader that regulates the cytoplasmic stability of methylated RNA. Here we show that YTHDC1 is a nuclear m6A reader and report the crystal structure of the YTH domain of YTHDC1 bound to m6A-containing RNA. We further determined the structure of another YTH domain, YTHDF1, and found that the YTH domain utilizes a conserved aromatic cage to specifically recognize the methyl group of m6A. Our structural characterizations of the YTHDC1-m6A RNA complex also shed light on the molecular basis for the preferential binding of the GG(m6A)C sequence by YTHDC1 and confirm the YTH domain as a specific m6A RNA reader. PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) was applied to human YTHDC1 protein to identify its binding sites.

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Escape from TGF-β-induced senescence promotes aggressive hallmarks in epithelial hepatocellular carcinoma cells

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CdGAP is a Talin-binding protein and a target of TGF-β signaling that promotes HER2-positive breast cancer growth and metastasis

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