ZEB1 drives epithelial-to-mesenchymal transition in lung cancer

Larsen, Jill E.; Nathan, Vaishnavi; Osborne, Jihan K.; Farrow, Rebecca K.; Deb, Dhruba; Sullivan, James P.; Dospoy, Patrick; Augustyn, Alexander; Hight, Suzie K.; Sato, Mitsuo; Girard, Luc; Behrens, Carmen; Wistuba, Ignacio I.; Gazdar, Adi F.; Hayward, Nicholas K.; Minna, John D.

doi:10.1172/jci76725

Cited by 280 publications

(225 citation statements)

References 55 publications

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“…Thus, they may bind to their target genes and recruit other coactivators that lead to upregulation of their target genes. Since ZNF281 is involved in inducing epithelial–mesenchymal transition (EMT) and promotes metastatis [52], anti-oncogenic effects of JQ1 on H23 cells may partly be due to downregulation of ZNF281, presumably through dissociation of BRD2, which may lead to disrupted EMT in lung cancer. Interestingly, a recent study showed that BRD2 activates expression of genes involved in EMT induction, whereas BRD3 and BRD4 exert opposite functions [53], supporting distinct roles of BRD2 among the somatic BET proteins [34,35,54,55].…”

Section: Discussionmentioning

confidence: 99%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.

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Section: Discussionmentioning

confidence: 99%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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“…These findings highlight the role of Spi-B in EMT program induction. Because Spi-B is not able to induce expression of vimentin or EMT-TFs in HBECs, and it has been documented that transformation of HBECs requires series oncogenic mutations and/or genetic manipulation accompanied with microenvironmental induction (36)(37)(38), it is possible that Spi-B may promote EMT through disruption of intercellular junctions, but this effect requires other oncogenic mutations or specific microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Spi-B–Mediated Silencing of Claudin-2 Promotes Early Dissemination of Lung Cancer Cells from Primary Tumors

Niu

et al. 2017

Cancer Research

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Dissociation from epithelial sheets and invasion through the surrounding stroma are critical early events during epithelial cancer metastasis. Here we find that a lymphocyte lineage-restricted transcription factor, Spi-B, is frequently expressed in human lung cancer tissues. The Spi-B-expressing cancer cells coexpressed vimentin but repressed E-cadherin and exhibited invasive behavior. Increased Spi-B expression was associated with tumor grade, lymphatic metastasis, and short overall survival. Mechanistically, Spi-B disrupted intercellular junctions and enhanced invasiveness by reconfiguring the chromatin structure of the tight junction gene claudin-2 (CLDN2) and repressing its transcription. These data suggest that Spi-B participates in mesenchymal invasion, linking epithelial cancer metastasis with a lymphatic transcriptional program.

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“…This allows the cells to be prone to TGF-β-induced EMT. The regulatory process of EMT induced by TGF-β in lung adenocarcinoma cells follows the common mechanisms with other types of cancers, which include the contribution of EMTrelated transcription factors, such as Snail and ZEB1 [116,117]. Likewise, TGF-β-induced EMT in lung adenocarcinoma cells is enhanced by co-stimulation with TNF-α or IL-1β secreted by other cells in the tumor microenvironment [118].…”

Section: Tgf-β-induced Target Gene Expression and Emt In Lung Adenocamentioning

confidence: 96%

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

et al. 2018

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Transforming growth factor (TGF)-β regulates a wide variety of cellular responses, including cell growth arrest, apoptosis, cell differentiation, motility, invasion, extracellular matrix production, tissue fibrosis, angiogenesis, and immune function. Although tumor-suppressive roles of TGF-β have been extensively studied and well-characterized in many cancers, especially at early stages, accumulating evidence has revealed the critical roles of TGF-β as a pro-tumorigenic factor in various types of cancer. This review will focus on recent findings regarding epithelial-mesenchymal transition (EMT) induced by TGF-β, in relation to crosstalk with some other signaling pathways, and the roles of TGF-β in lung and pancreatic cancers, in which TGF-β has been shown to be involved in cancer progression. Recent findings also strongly suggested that targeting TGF-β signaling using specific inhibitors may be useful for the treatment of some cancers. TGF-β plays a pivotal role in the differentiation and function of regulatory T cells (Tregs). TGF-β is produced as latent high molecular weight complexes, and the latent TGF-β complex expressed on the surface of Tregs contains glycoprotein A repetitions predominant (GARP, also known as leucine-rich repeat containing 32 or LRRC32). Inhibition of the TGF-β activities through regulation of the latent TGF-β complex activation will be discussed.

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ZEB1 drives epithelial-to-mesenchymal transition in lung cancer

Abstract: able slope). Kaplan-Meier survival plots and log-rank tests were used to assess differences in outcome. A P value of less than 0.05 was considered significant.Study approval. All animal studies were approved by the Institutional Animal Care and Use Committee at

Cited by 280 publications

References 55 publications

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Spi-B–Mediated Silencing of Claudin-2 Promotes Early Dissemination of Lung Cancer Cells from Primary Tumors

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

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