Foxc1 Expression in Early Osteogenic Differentiation Is Regulated by BMP4‐SMAD Activity

Hopkins, Alexander C.; Mirzayans, Farideh; Berry, Fred B.

doi:10.1002/jcb.25464

Cited by 35 publications

(39 citation statements)

References 33 publications

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“…Moreover, interleukin-8 (IL-8) induces FOXC1 expression through activation of phosphoinositide 3-kinase signaling 40, suggesting that tumor inflammation is an induction condition for FOXC1 expression. Besides, FOXC1 expression is regulated by BMP4 in early osteogenic differentiation 41. In the present study, we show that hypoxia induces FOXC1 expression in the tumor microenvironment.…”

Section: Discussionsupporting

confidence: 62%

Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression

Lin¹,

Shyu²,

Chang³

et al. 2017

Theranostics

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Forkhead box C1 (FOXC1) is a member of the forkhead family of transcription factors that are characterized by a DNA-binding forkhead domain. Increasing evidence indicates that FOXC1 is involved in tumor progression. However, the role of tumor hypoxia in FOXC1 regulation and its impact on lung cancer progression are unclear. Here, we report that FOXC1 was upregulated in hypoxic areas of lung cancer tissues from rodents or humans. Hypoxic stresses significantly induced FOXC1 expression. Moreover, hypoxia activated FOXC1 transcription via direct binding of hypoxia-inducible factor-1α (HIF-1α) to the hypoxia-responsive element (HRE) in the FOXC1 promoter. FOXC1 gain-of-function in lung cancer cells promoted cell proliferation, migration, invasion, angiogenesis, and epithelial-mesenchymal transition in vitro. However, a knockdown of FOXC1 in lung cancer cells inhibited these effects. Notably, knockdown of tumor hypoxia-induced FOXC1 expression via HIF-1-mediated FOXC1 shRNAs in lung cancer xenograft models suppressed tumor growth and angiogenesis. Finally, systemic delivery of FOXC1 siRNA encapsulated in lipid nanoparticles inhibited tumor growth and increased survival time in lung cancer-bearing mice. Taken together, these data indicate that FOXC1 is a novel hypoxia-induced transcription factor and plays a critical role in tumor microenvironment-promoted lung cancer progression. Systemic FOXC1 blockade therapy may be an effective therapeutic strategy for lung cancer.

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Section: Discussionsupporting

confidence: 62%

Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression

Lin¹,

Shyu²,

Chang³

et al. 2017

Theranostics

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“…whereas non-differentiated cells generated ATP through oxidative phosphorylation (34). however animals harboring deficits in any one of these genes exhibited significant defects in bone development, formation, or mineralization (42,66,93). Sodium fluoride (NaF) is an osteoanabolic that increases bone mass but the newly formed bone lacks normal structure and strength (10,86,99).…”

Section: Discussionmentioning

confidence: 99%

Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality

Shao

Wichern

Childress

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor nuclear matrix protein 4 ( Nmp4, Zfp384, Ciz, ZNF384) respond to several classes of osteoporosis drugs with enhanced bone formation compared with wild-type (WT) animals. Nmp4−/− mesenchymal stem/progenitor cells (MSPCs) exhibit an accelerated and enhanced mineralization during osteoblast differentiation. To address the mechanisms underlying this hyperanabolic phenotype, we carried out RNA-sequencing and molecular and cellular analyses of WT and Nmp4−/− MSPCs during osteogenesis to define pathways and mechanisms associated with elevated matrix production. We determined that Nmp4 has a broad impact on the transcriptome during osteogenic differentiation, contributing to the expression of over 5,000 genes. Phenotypic anchoring of transcriptional data was performed for the hypothesis-testing arm through analysis of cell metabolism, protein synthesis and secretion, and bone material properties. Mechanistic studies confirmed that Nmp4−/− MSPCs exhibited an enhanced capacity for glycolytic conversion: a key step in bone anabolism. Nmp4−/− cells showed elevated collagen translation and secretion. The expression of matrix genes that contribute to bone material-level mechanical properties was elevated in Nmp4−/− cells, an observation that was supported by biomechanical testing of bone samples from Nmp4−/− and WT mice. We conclude that loss of Nmp4 increases the magnitude of glycolysis upon the metabolic switch, which fuels the conversion of the osteoblast into a super-secretor of matrix resulting in more bone with improvements in intrinsic quality.

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“…Our previous research showed that Foxc1 expression was differentially regulated by BMP signalling at different stages of osteoblast differentiation [Hopkins et al, 2016] . Foxc1 expression is induced by BMP4 in C2C12 cells and is required for BMP4-induced osteoblast differentiation of these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Primary micromass cultures from Foxc1 -/fail to induce chondrogenic nodules in response to BMP2 treatment [Kume et al, 1998] and Foxc1 function is required for activation of BMP-responsive genes in the mouse calvarium [Rice et al, 2003] . We have previously demonstrated that Foxc1 is a target for BMP induced gene expression during early stages of osteoblast differentiation of mesenchymal progenitor cells [Hopkins et al, 2016] . Foxc1 mRNA levels increased in BMP4-treated C2C12 cells through the direct binding of SMAD factors to the Foxc1 regulatory region.…”

Section: Introductionmentioning

confidence: 99%

FOXC1 negatively regulates BMP-SMAD activity and Id1 expression during osteoblast differentiation

Caddy

Luoma

Berry

2019

Preprint

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Bone morphogenetic proteins regulate a diverse range of biological processes through their activation of SMAD1, 5, or 8 proteins that in turn regulate gene expression. These SMAD transcription factors achieve a layer of functional specificity in different cells types largely through actions with additional transcriptional regulatory molecules. In this report we demonstrate that the Forkhead Box C1 (FOXC1) transcription factor can modulate BMP signalling to impair expression of BMP4-responsive genes and prevent efficient osteoblast differentiation. We demonstrate that repression occurs downstream of BMP signalling and impacts the ability SMAD1 or 5 to activate gene expression. Repression of SMAD activity requires FOXC1 DNA-binding capacity and the transcriptional inhibitory domain of FOXC1.We report that FOXC1 inhibits BMP4 induction of Id1 expression and identify a motif in the regulatory region of mouse Id1 gene that FOXC1 binds. We determine that this inhibition by FOXC1 binding does not affect SMAD1, 5, or 8 binding to its target sequence in the Id1 gene.Finally we determine that elevated expression of FOXC1 can reduces expression osteogenic differentiation genes in mouse embryonic stems directed to the osteoblast lineage through BMP4 treatment. Together, these findings indicate that FOXC1 can negative regulate certain aspects of BMP4 signalling required for osteoblast differentiation. We propose that FOXC1 acts to attenuate the initial BMP-activated pathways that establishes osteoblast differentiation and allow for terminal osteoblast differentiation to conclude.

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Foxc1 Expression in Early Osteogenic Differentiation Is Regulated by BMP4‐SMAD Activity

Cited by 35 publications

References 33 publications

Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression

Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression

Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality

FOXC1 negatively regulates BMP-SMAD activity and Id1 expression during osteoblast differentiation

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