Inhibition of EP300 and DDR1 synergistically alleviates pulmonary fibrosis in vitro and in vivo

Jia, Tan; Zhang, Min; Wen, Zhijie; Wang, Baoxue; Zhang, Lei; Ou, Yu; Xu, Tao; Yu, Xiaoping; Jiang, Qinglin

doi:10.1016/j.biopha.2018.07.132

Cited by 34 publications

(22 citation statements)

References 41 publications

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“…In summary, by exploiting the availability of samples from patients with DD and a combination of epigenetic and transcriptional profiling studies, we defined EP300 as an important regulator of human fibrosis that directs diverse cellular processes in myofibroblasts. There are supporting data showing that pharmacological inhibition of EP300 is effective in murine models of pulmonary fibrosis (75,76). However, the many targets of epigenetic regulators suggest their long-term global inhibition may result in off-target effects.…”

Section: Discussionmentioning

confidence: 91%

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Williams

McCann

Cabrita

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren’s disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1. Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren’s nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

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Section: Discussionmentioning

confidence: 91%

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Williams

McCann

Cabrita

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Third, as H3K27ac was reduced after JQ1 treatment, we also investigated the effect of CBP30, a highly selective inhibitor of the HAT protein complex CBP/p300, which induces the H3K27ac mark [ 86 ]. The compound has been suggested to reduce fibrosis because it either directly or together with an inhibitor of the main collagen receptor discoidin domain receptor 1 (DDR1) attenuated lung inflammation and fibroblast activation in idiopathic pulmonary fibrosis [ 81 , 87 ]. In addition, a transcriptome analysis found that multiple pro-fibrotic pathways were dysregulated in CBP30-treated myofibroblasts derived from patients with Dupuytren’s disease [ 88 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response

Liu

Tóth

Bakr

et al. 2021

Cancers

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Radiotherapy, a common component in cancer treatment, can induce adverse effects including fibrosis in co-irradiated tissues. We previously showed that differential DNA methylation at an enhancer of diacylglycerol kinase alpha (DGKA) in normal dermal fibroblasts is associated with radiation-induced fibrosis. After irradiation, the transcription factor EGR1 is induced and binds to the hypomethylated enhancer, leading to increased DGKA and pro-fibrotic marker expression. We now modulated this DGKA induction by targeted epigenomic and genomic editing of the DGKA enhancer and administering epigenetic drugs. Targeted DNA demethylation of the DGKA enhancer in HEK293T cells resulted in enrichment of enhancer-related histone activation marks and radiation-induced DGKA expression. Mutations of the EGR1-binding motifs decreased radiation-induced DGKA expression in BJ fibroblasts and caused dysregulation of multiple fibrosis-related pathways. EZH2 inhibitors (GSK126, EPZ6438) did not change radiation-induced DGKA increase. Bromodomain inhibitors (CBP30, JQ1) suppressed radiation-induced DGKA and pro-fibrotic marker expression. Similar drug effects were observed in donor-derived fibroblasts with low DNA methylation. Overall, epigenomic manipulation of DGKA expression may offer novel options for a personalized treatment to prevent or attenuate radiotherapy-induced fibrosis.

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“…ABL2 signaling regulates fibroblast proliferation [ 72 ]. DDR1 inhibitors reduce fibrosis in other fibrotic diseases [ 73 , 74 , 75 , 76 ]. FYN regulates downstream serine-threonine kinase activities involved in the modulation of fibroblast–epithelial cell interactions and the promotion of organ fibrosis [ 77 , 78 ].…”

Section: Discussionmentioning

confidence: 99%

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases

Creeden

Alganem

Imami

et al. 2020

IJMS

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Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.

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Inhibition of EP300 and DDR1 synergistically alleviates pulmonary fibrosis in vitro and in vivo

Cited by 34 publications

References 41 publications

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases

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