Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis

Evans, Iona; Barnes, Josephine; Garner, Ian; Pearce, David R.; Maher, Toby M.; Xu, Shiwen; Renzoni, Elisabetta A.; Wells, Adrian; Denton, Christopher P.; Laurent, Geoffrey J.; Abraham, David; McAnulty, Robin J.

doi:10.1042/cs20150697

Cited by 64 publications

(55 citation statements)

References 47 publications

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“…Both are in clinical trials for treatment of solid tumors including lung (99, 100). Present evidence strongly supports a role for hypermethylated specific genes, such as Thy-1(78–80), COX-2 (81), PTGER2 (82), and p14 ARF (20) in regulating fibroblast phenotype and favoring fibrosis development. There are many studies carried out testing the effects of DNMT inhibitors on fibrotic diseases (45, 101).…”

Section: Possible Therapeutic Approachessupporting

confidence: 73%

“…One study shows COX-2 promoter DNA has more methylated copies in IPF fibroblasts than controls (58). Another report shows no difference compared to control; while 5-AZAdc, through demethylating the transcriptional regulatory factor c8orf4 of COX-2, indirectly increases the reduced level of COX-2 mRNA in a dose dependent pattern (81). This study also shows 5-AZAdc decreases collagen mRNA expression and restores sensitivity to apoptosis in IPF fibroblasts (81).…”

Section: Dna Methylation In Pulmonary Fibrosismentioning

confidence: 99%

“…Another report shows no difference compared to control; while 5-AZAdc, through demethylating the transcriptional regulatory factor c8orf4 of COX-2, indirectly increases the reduced level of COX-2 mRNA in a dose dependent pattern (81). This study also shows 5-AZAdc decreases collagen mRNA expression and restores sensitivity to apoptosis in IPF fibroblasts (81). This discrepancy suggested different mechanisms for COX-2 silencing in fibrotic lung fibroblasts.…”

Section: Dna Methylation In Pulmonary Fibrosismentioning

confidence: 99%

“…There are a number of specific genes that demonstrate DNA hypermethylation, corresponding to their reduced expression in IPF, such as Thy-1 (78–80), COX-2 (81), prostaglandin receptor 2 (PTGER2) (82), and p14 ARF (20) (Table 1). Reduced expression of these genes directly stimulates fibrogenesis, perpetuates fibroblast activation, and promotes resistance to apoptosis.…”

Section: Dna Methylation In Pulmonary Fibrosismentioning

confidence: 99%

“…Their synthesis and action are diminished in pulmonary fibrosis (81, 85). PGE2 increases lung fibroblasts global and gene-specific DNA methylation, such as IGFBP2 and MGMT, through upregulation of DNMT3a expression and activity (86).…”

Section: Dna Methylation In Pulmonary Fibrosismentioning

confidence: 99%

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DNA methylation regulated gene expression in organ fibrosis

Zhang

Lyu

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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DNA methylation is a major epigenetic mechanism to regulate gene expression. Epigenetic regulation, including DNA methylation, histone modifications and RNA interference, results in heritable changes in gene expression independent of alterations in DNA sequence. Epigenetic regulation often occurs in response to aging and environment stimuli, including exposures and diet. Studies have shown that DNA methylation is critical in the pathogenesis of fibrosis involving multiple organs sytems, contributing to significant morbidity and mortality. Aberrant DNA methylation can silence or activate gene expression patterns that drive the fibrosis process. Fibrosis is a pathological wound healing process in response to chronic injury. It is characterized by excessive extracellular matrix production and accumulation, which eventually affects organ architecture and results in organ failure. Fibrosis can affect a wide range of organs, including the heart and lungs, and have limited therapeutic options. DNA methylation, like other epigenetic process, is reversible, therefore regarded as attractive therapeutic interventions. Although epigenetic mechanisms are highly interactive and often reinforcing, this review discusses DNA methylation-dependent mechanisms in the pathogenesis of organ fibrosis, with focus on cardiac and pulmonary fibrosis. We discuss specific pro- and anti-fibrotic genes and pathways regulated by DNA methylation in organ fibrosis; we further highlight the potential benefits and side-effects of epigenetic therapies in fibrotic disorders.

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Section: Possible Therapeutic Approachessupporting

confidence: 73%

Section: Dna Methylation In Pulmonary Fibrosismentioning

confidence: 99%

Section: Dna Methylation In Pulmonary Fibrosismentioning

confidence: 99%

Section: Dna Methylation In Pulmonary Fibrosismentioning

confidence: 99%

Section: Dna Methylation In Pulmonary Fibrosismentioning

confidence: 99%

See 3 more Smart Citations

DNA methylation regulated gene expression in organ fibrosis

Zhang

Lyu

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Exploring hTERT promoter methylation in cutaneous T‐cell lymphomas

et al. 2021

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Cutaneous T-cell lymphomas (CTCL) are telomerase-positive tumors expressing hTERT, although neither gene rearrangement/amplification nor promoter hotspot mutations could explain the hTERT re-expression. As the hTERT promoter is rich in CpG, we investigated the contribution of epigenetic mechanisms in its reexpression. We analyzed hTERT promoter methylation status in CTCL cells compared to healthy cells. Gene-specific methylation analyses revealed a common methylation pattern exclusively in tumor cells. This methylation pattern encompassed a hypermethylated distal region from-650bp to-150bp and a hypomethylated proximal region from-150bp to +150bp. Interestingly, the hypermethylated region matches with the recently named TERT Hypermethylated Oncogenic Region (THOR). THOR has been associated with telomerase reactivation in many cancers, but it has so far not been reported in cutaneous lymphomas. Additionally, we assessed the effect on THOR of two histone deacetylase inhibitors (HDACi), romidepsin and vorinostat, both approved for CTCL treatment as well as a DNA methyltransferase inhibitor (DNMTi) 5-azacytidine, unapproved for CTCL. Contrary to our expectations, the findings reported herein revealed that THOR methylation is relatively stable under these epigenetic drugs' pressure, whereas these drugs reduced the hTERT gene expression.

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Therapeutic induction of Bcl2‐associated athanogene 3‐mediated autophagy in idiopathic pulmonary fibrosis

Chillappagari

Schwarz

Kesireddy

et al. 2022

Clinical & Translational Med

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IPF-fibroblasts are refractory to BAG3-mediated autophagy. Knock down of BAG3 per se in IPF fibroblasts does not ameliorate BAG3-mediated autophagy. Therapeutic intervention (pirfenidone+5-azacytidine or pirfenidone+cantharidin) sensitizes IPF fibroblasts to BAG3-mediated autophagy. Drug-induced sensitization of BAG3-mediated autophagy in precision cut lung slices of IPF patients alleviates fibroblast proliferation and collagen deposition.

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Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis

Cited by 64 publications

References 47 publications

DNA methylation regulated gene expression in organ fibrosis

DNA methylation regulated gene expression in organ fibrosis

Exploring hTERT promoter methylation in cutaneous T‐cell lymphomas

Therapeutic induction of Bcl2‐associated athanogene 3‐mediated autophagy in idiopathic pulmonary fibrosis

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