Similar Datasets
Project description:FOXA1, a transcription factor involved in epigenetic reprogramming, is crucial for breast cancer progression. However, the mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) of FOXA1 promotes breast cancer metastasis by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr432, Ser441, and Ser443 regulates the stability of FOXA1 and promotes its assembly with chromatin. O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor methyl-CpG binding protein 2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including EPB41L3 and COL9A2. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo. Our data establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and indicate that targeting O-GlcNAcylation is a therapeutic strategy for metastatic breast cancer.
| S-EPMC10438466 | biostudies-literature
Project description:The forkhead protein FOXA1 has been found to play a critical role in orchestrating hormonal-signaling network and to function as a pioneer factor to regulate breast-specific gene expression,However, whether interplay between O-GlcNAcylation and FOXA1 affects the genome-wide transcriptional activity of this TF and subsequently orchestrates downstream gene expression networks in breast cancer progression needs further elucidation.
2022-12-21 | PXD039019 |
Project description:The transcription factor FOXA1, which functions in epigenetic reprogramming, plays a critical role in breast cancer progression. However, the molecular mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-GlcNAcylation of FOXA1 increases breast cancer metastasis capacity by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr432, Ser441 and Ser443 regulates the stability of FOXA1 and promotes its assembly with chromatin in breast cancer cells. We provide evidence that O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor MECP2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including EPB41L3 and COL9A2. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo.
2023-01-02 | GSE221933 | GEO
Project description:The transcription factor FOXA1, which functions in epigenetic reprogramming, plays a critical role in breast cancer progression. However, the molecular mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-GlcNAcylation of FOXA1 increases breast cancer metastasis capacity by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr432, Ser441 and Ser443 regulates the stability of FOXA1 and promotes its assembly with chromatin in breast cancer cells. We provide evidence that O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor MECP2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including EPB41L3 and COL9A2. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo.
2023-01-02 | GSE221934 | GEO
Project description:FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer.
| PRJNA916875 | ENA
Project description:FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer [ChIP-seq]
| PRJNA916878 | ENA
Project description:FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer [RNA-seq]
| PRJNA916880 | ENA
Project description:O-GlcNAcylation is a post-translational modification that regulates a broad range of nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes. Although previous studies have shown that increased levels of global O-GlcNAcylation and O-GlcNActransferase are linked to the incidence of metastasis in triple negative breast cancer (TNBC) patients, the molecular basis behind this is not fully understood. In this study, we have determined that the TAK1 binding protein 3 (TAB3) was O-GlcNAcylated at Ser408 by OGT in the TNBC, which was required for its Thr404 phosphorylation, TAK1 activation and downstream nuclear factor kappa B (NF-?B) activation in TNBC. O-GlcNAcylation of TAB3 was induced by p38 MAPK and it in turn enhances the TAK1 mediated p38MAPK activation, which forms the positive feedback loop in TAB3mediated NF-?B activation. In TNBC, TAB3O-GlcNAcylationmediated cell migration and invasion by activating its downstream NF-?B. The expression of TAB3 O-GlcNAcylation increased in TNBC patients, and it was significantly correlated with poor prognoses of the patients. Our study provides insights into the mechanism of TAB3 regulating activity and suggests its important implications in TNBC metastasis.
| S-EPMC5008402 | biostudies-literature
Project description:The heterogeneous breast cancers can be classified into different subtypes according to their histopathological characteristics and molecular signatures. Foxa1 expression is linked with luminal breast cancer (LBC) with good prognosis, whereas Twist1 expression is associated with basal-like breast cancer (BLBC) with poor prognosis owing to its role in promoting epithelial-to-mesenchymal transition (EMT), invasiveness and metastasis. However, the regulatory and functional relationships between Twist1 and Foxa1 in breast cancer progression are unknown. In this study, we demonstrate that in the estrogen receptor (ERα)-positive LBC cells Twist1 silences Foxa1 expression, which has an essential role in relieving Foxa1-arrested migration, invasion and metastasis of breast cancer cells. Mechanistically, Twist1 binds to Foxa1 proximal promoter and recruits the NuRD transcriptional repressor complex to de-acetylate H3K9 and repress RNA polymerase II recruitment. Twist1 also silences Foxa1 promoter by inhibiting AP-1 recruitment. Twist1 expression in MCF7 cells silenced Foxa1 expression, which was concurrent with the induction of EMT, migration, invasion and metastasis of these cells. Importantly, restored Foxa1 expression in these cells largely inhibited Twist1-promoted migration, invasion and metastasis. Restored Foxa1 expression did not change the Twist1-induced mesenchymal cellular morphology and the expression of Twist1-regulated E-cadherin, β-catenin, vimentin and Slug, but it partially rescued Twist1-silenced ERα and cytokeratin 8 expression and reduced Twist1-induced integrin α5, integrin β1 and MMP9 expression. In a xenografted mouse model, restored Foxa1 also increased Twist1-repressed LBC markers and decreased Twist1-induced BLBC markers. Furthermore, Twist1 expression is negatively correlated with Foxa1 in the human breast tumors. The tumors with high Twist1 and low Foxa1 expressions are associated with poor distant metastasis-free survival. These results demonstrate that Twist1's silencing effect on Foxa1 expression is largely responsible for Twist1-induced migration, invasion and metastasis, but less responsible for Twist1-induced mesenchymal morphogenesis and expression of certain EMT markers.
| S-EPMC5311074 | biostudies-literature
Project description:Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient's primary tumour was most strongly correlated with later metastatic relapse. Here we show that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by knockdown of asparagine synthetase, treatment with l-asparaginase, or dietary asparagine restriction reduces metastasis without affecting growth of the primary tumour, whereas increased dietary asparagine or enforced asparagine synthetase expression promotes metastatic progression. Altering asparagine availability in vitro strongly influences invasive potential, which is correlated with an effect on proteins that promote the epithelial-to-mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression.
| S-EPMC5898613 | biostudies-literature