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RNA N6-methyladenosine reader YTHDC1 is essential for TGF-beta-mediated metastasis of triple negative breast cancer [RIP-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: GSE193154 | 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 [RNA-Seq]

2023-03-25 | GSE193153 | GEO

Expression data from Control and Six1 expressing MCF7 cells

Project description:Inappropriate activation of developmental pathways is a well-recognized tumor-promoting mechanism. Here we show that overexpression of the homeoprotein Six1, normally a developmentally restricted transcriptional regulator, increases Transforming Growth Factor-beta (TGF-beta) signaling in mammary carcinoma cells and induces an epithelial to mesenchymal transition (EMT) that is in part dependent on its ability to increase TGF-beta signaling. TGF-beta signaling and EMT have been implicated in metastatic dissemination of carcinoma. Using spontaneous and experimental metastasis mouse models, we demonstrate that Six1 overexpression promotes breast cancer metastasis. In addition, we show that, like its induction of EMT, Six1-induced experimental metastasis is dependent on its ability to activate TGF-beta signaling. Importantly, in human breast cancers Six1 significantly correlates with nuclear Smad3, and thus increased TGF-beta signaling. Further, breast cancer patients whose tumors overexpress Six1 have a shortened time to relapse and metastasis, and an overall decrease in survival. Finally, we show that the effects of Six1 on tumor progression likely extend beyond breast cancer, since its overexpression correlates with adverse outcomes in numerous other cancers, including brain, cervical, prostate, colon, kidney, and liver, amongst others. Our findings argue that Six1, acting through TGF-beta signaling and EMT, is a powerful and global promoter of cancer metastasis.

2010-08-21 | GSE23655 | GEO

RNA-seq analysis of A549 cells harboring Smad3 R104K A105P mutation.

Project description:Transforming growth factor-beta (TGF-beta) transmits signals that facilitate cancer progression. Especially, epithelial-mesenchymal transition (EMT) induced by TGF-beta is considered to crucially contribute to the malignant phenotype of cancer cells. Here we report that the EMT-associated cellular responses induced by TGF-beta are mediated through distinct signaling pathways that diverge at Smad3; cell motility and epithelial marker downregulation are Smad3-dependent while mesenchymal marker induction is not. Furthermore, using a chimeric protein approach in SMAD3 knockout A549 cells, we found that the beta 4 region in the MH1 domain of Smad3 is indispensable for TGF-beta–induced cell motility, but not for epithelial marker downregulation. A transcriptome analysis was performed using A549 cells expressing Smad3 mutant of the MH1 domain.

2021-03-10 | GSE152015 | GEO

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.

2019-04-12 | GSE128965 | GEO

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

2019-04-12 | GSE129008 | GEO

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

Project description:Aberrant SMAD3 activation has been implicated as a driving event in cancer metastasis. However, the drivers of SMAD3 activation are poorly defined. Here, we identify SMAD3 as a non-histone substrate of lysine acetyltransferase 6A (KAT6A). The acetylation of SMAD3 at K20 and K117 by KAT6A with promotes SMAD3 association with oncogenic H3K23ac reader TRIM24 and upregulation of immune response-related cytokines. This event in turn leads to enhanced myeloid-derived suppressor cell (MDSC) recruitment and triple-negative breast cancer (TNBC) metastasis. Inhibiting KAT6A in combination with anti-PD-L1 therapy in treating breast cancer xenograft-bearing animals markedly attenuates TNBC metastasis and provides a significant survival benefit. Thus, our work presents an KAT6A acetylation-dependent regulatory mechanism governing SMAD3 oncogenic function and provides insight into how targeting an epigenetic factor with immunotherapies enhances the anti-metastasis efficacy.

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.

2014-09-18 | E-GEOD-58352 | biostudies-arrayexpress

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

Project description:Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastasis, which is the leading cause of death in breast cancer patients. We show that Cdc42 GTPase-activating protein (CdGAP) promotes tumor formation and metastasis to lungs in the HER2-positive (HER2+) murine breast cancer model. CdGAP facilitates intravasation, extravasation, and growth at metastatic sites. CdGAP depletion in HER2+ murine primary tumors mediates crosstalk with a Dlc1-RhoA pathway and is associated with a transforming growth factor-β (TGF-β)-induced EMT transcriptional signature. To further delineate the molecular mechanisms underlying the pro-migratory role of CdGAP in breast cancer cells, we searched for CdGAP interactors by performing a proteomic analysis using HEK293 cells overexpressing GFP-CdGAP. We found that CdGAP interacts with the adaptor Talin to modulate focal adhesion dynamics and integrin activation. Moreover, HER2+ breast cancer patients with high CdGAP mRNA expression combined with a high TGF-β-EMT signature are more likely to present lymph node invasion. Our results suggest CdGAP as a candidate therapeutic target for HER2+ metastatic breast cancer by inhibiting TGF-β and Integrin/Talin signaling pathways.

2023-07-14 | PXD043376 | Pride

Expression data from TGF-beta treated Panc-1 pancreatic adenocarcinoma cell line

Project description:TGF-beta treatment of Panc-1 pancreatic adenocarcinoma cell line on Affymetrix HG_U133_plus_2 arrays; triplicate experiments. The goal of the experiment is to profile temporal gene expression changes during TGF-beta-induced epithelial-mesenchymal transition (EMT). During EMT cancer cells lose their epithelial specifc proteins and gain mesenchymal proteins to acquire migratory and invasive phenotype essential for metastasis. Human Panc-1 pancreatic adenocarcinoma cell line was treated with 5 ng/mL TGF-beta for 48 h to induce EMT. The experiment was repeated 3 times. Samples were assayed using Affymetrix HG_U133_plus_2 arrays with 54675 probe-sets, using standard techniques. Human Panc-1 pancreatic adenocarcinoma cell line was treated with 5 ng/mL TGF-beta for 48 h. The experiment was repeated 3 times. Samples were assayed using Affymetrix HG_U133_plus_2 arrays with 54675 probe-sets, using standard techniques.

2010-09-03 | E-GEOD-23952 | biostudies-arrayexpress

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