Forkhead factors regulate epithelial plasticity: Impact on cancer progression

Feuerborn, Alexander; Küffer, Stefan; Gröne, Hermann Josef

doi:10.4161/cc.10.15.16306

Cited by 6 publications

(6 citation statements)

References 58 publications

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“…In support of this hypothesis, modulation of FOXF1 expression levels in human fibroblasts did not induce changes in the expression levels of ITGB3 or GH2, two genes shown to be direct FOXF1 transcriptional targets in mouse fetal lung mesenchyme or human embryonic cells (26,21), whereas analysis of COL1A1 or ARPC2 promoter regions and introns did not reveal the presence of FOXF1 consensus binding sites (12). The mechanisms by which FOXF1 repressed COL1 and ARPC2 are unclear.…”

Section: Discussionsupporting

confidence: 48%

Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro

Melboucy‐Belkhir

Pradère

Tadbiri

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Aberrant expression of master phenotype regulators or alterations in their downstream pathways in lung fibroblasts may play a central role in idiopathic pulmonary fibrosis (IPF). Interrogating IPF fibroblast transcriptome datasets, we identified Forkhead Box F1 (FOXF1), a DNA-binding protein required for lung development, as a candidate actor in IPF. Thus we determined FOXF1 expression levels in fibroblasts cultured from normal or IPF lungs in vitro, and explored FOXF1 functions in these cells using transient and stable loss-of-function and gain-of-function models. FOXF1 mRNA and protein were expressed at higher levels in IPF fibroblasts compared with normal fibroblasts (mRNA: ϩ44%, protein: ϩ77%). Immunohistochemistry showed FOXF1 expression in nuclei of bronchial smooth muscle cells, endothelial cells, and lung fibroblasts including fibroblastic foci of IPF lungs. In normal lung fibroblasts, FOXF1 repressed cell growth and expression of collagen-1 (COL1) and actin-related protein 2/3 complex, subunit 2 (ARPC2). ARPC2 knockdown inhibited cell growth and COL1 expression, consistent with FOXF1 acting in part through ARPC2 repression. In IPF fibroblasts, COL1 and ARPC2 repression by FOXF1 was blunted, and FOXF1 did not repress growth. FOXF1 expression was induced by the antifibrotic mediator prostaglandin E 2 and repressed by the profibrotic cytokine transforming growth factor-␤1 in both normal and IPF lung fibroblasts. Ex vivo, FOXF1 knockdown conferred CCL-210 lung fibroblasts the ability to implant in uninjured mouse lungs. In conclusion, FOXF1 functions and regulation were consistent with participation in antifibrotic pathways. Alterations of pathways downstream of FOXF1 may participate to fibrogenesis in IPF fibroblasts.

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Section: Discussionsupporting

confidence: 48%

Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro

Melboucy‐Belkhir

Pradère

Tadbiri

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Several FOX family members including FOXQ1, FOXC2 and FOXA1 have been positively or negatively implicated in EMT and/or CSC development. 48 It is likely that several family members act to regulate accessibility and/or expression upon stimulation and progression along the CSC pathway and that there is some level of redundancy. However, the results presented here show that FOXQ1 and FOXN2 have non-redundant roles in optimal expression of several CSC-associated genes and the protein levels of fibronectin and laminin V.…”

Section: Discussionmentioning

confidence: 99%

“… 52 FOXQ1 depletion in MDA-MB-231 cells increases epithelial morphology and reduces invasiveness, 32 and it also plays a role in other metastasis models. 48 It has been suggested that this role may be mediated through its repression of E-cadherin via direct binding to an upstream E-box. 48 However, the identification of FOX motifs in regulatory regions of CSC-associated genes raises the possibility that an important role of FOXQ1 and FOXN2 in CSC formation is mediated via their positive regulation of the expression of these genes.…”

Section: Discussionmentioning

confidence: 99%

“… 48 It has been suggested that this role may be mediated through its repression of E-cadherin via direct binding to an upstream E-box. 48 However, the identification of FOX motifs in regulatory regions of CSC-associated genes raises the possibility that an important role of FOXQ1 and FOXN2 in CSC formation is mediated via their positive regulation of the expression of these genes. The most distinguishing feature of the FOX motif is that it is enriched in the newly accessible regions closer to genes with higher expression in CSCs than NCSCs.…”

Section: Discussionmentioning

confidence: 99%

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Identification of chromatin accessibility domains in human breast cancer stem cells

Hardy

et al. 2016

Nucleus

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Epithelial-to-mesenchymal transition (EMT) is physiological in embryogenesis and wound healing but also associated with the formation of cancer stem cells (CSCs). Many EMT signaling pathways are implicated in CSC formation, but the precise underlying mechanisms of CSC formation remain elusive. We have previously demonstrated that PKC is critical for EMT induction and CSC formation in inducible breast EMT/CSC models. Here, we used formaldehyde-assisted isolation of regulatory elements-sequencing (FAIRE-seq) to investigate DNA accessibility changes after PKC activation and determine how they influence EMT and CSC formation. During EMT, DNA accessibility principally increased in regions distant from transcription start sites, low in CpG content, and enriched with chromatin enhancer marks. ChIP-sequencing revealed that a subset of these regions changed from poised to active enhancers upon stimulation, with some even more acteylated in CSCs. While regions with increased accessibility were enriched for FOX, AP-1, TEAD, and TFAP2 motifs, those containing FOX and AP-1 motif were associated with increased expression of CSC-associated genes, while those with TFAP2 were associated with genes with increased expression in non-CSCs. Silencing of 2 members of the FOX family, FOXN2 and FOXQ1, repressed CSCs and the mesenchymal phenotype and inhibited the CSC gene signature. These novel, PKC-induced DNA accessibility regions help explain how the epigenomic plasticity of cells undergoing EMT leads to CSC gene activation.

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“…42,49,56,57 To cite some examples, so-called "pioneer factors," such as forkhead factors, 58 displace nucleosomes upon binding to the genome, freeing neighboring DNA sequences from nucleosomal occlusion, thus assisting in the occupation of the neighboring sites by TFs whose binding activity is inhibited by nucleosomes. [58][59][60] One of such specialized TFs, FoxA1, assists in genomic binding of ERα and AR in FoxA1-expressing cells. 22 Another case would be TFs that provide surfaces for TF recognition.…”

Section: The Importance Of the Own Cognate Dna Motif In The Generatiomentioning

confidence: 99%

Cistrome plasticity and mechanisms of cistrome reprogramming

García-Bassets

Wang

2012

Cell Cycle

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Mammalian genomes contain thousands of cis-regulatory elements for each transcription factor (TF), but TFs only occupy a relatively small subset referred to as cistrome. Recent studies demonstrate that a TF cistrome might differ among different organisms, tissue types and individuals. In a cell, a TF cistrome might differ among different physiological states, pathological stages and between physiological and pathological conditions. It is, therefore, remarkable how highly plastic these binding profiles are, and how massively they can be reprogrammed in rapid response to intra/extracellular variations and during cell identity transitions and evolution. Biologically, cistrome reprogramming events tend to be followed by changes in transcriptional outputs, thus serving as transformative mechanisms to synchronically alter the biology of the cell. In this review, we discuss the molecular basis of cistrome plasticity and attempt to integrate the different mechanisms and biological conditions associated with cistrome reprogramming. Emerging data suggest that, when altered, these reprogramming events might be linked to tumor development and/or progression, which is a radical conceptual change in our mechanistic understanding of cancer and, potentially, other diseases.

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Forkhead factors regulate epithelial plasticity: Impact on cancer progression

Cited by 6 publications

References 58 publications

Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro

Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro

Identification of chromatin accessibility domains in human breast cancer stem cells

Cistrome plasticity and mechanisms of cistrome reprogramming

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