Overexpression of EP and DDR has been
Overexpression of EP300 and DDR1 has been sporadically reported in the pathogenesis of pulmonary fibrosis and other fibrotic diseases. Zeng et al. reported that EP300 was increased in TGF-β1 treated lung fibroblasts and mediated decreases of SIRT1 expression. Bhattacharyya et al. found that both EP300 overexpression stimulated by TGF-β1 via the Egr-1 pathway and EP300 reversely enhanced Smad-dependent TGF-β signaling. Borza et al. reported that DDR1 was involved in several diseases beyond pulmonary fibrosis, including cancer, osteoarthritis, renal, liver injury, and atherosclerosis. In agreement with our previous report, we confirmed that DDR1 and EP300 overexpression in lung tissues of IPF patients may relate to the elevation of inflammation and cytokines. Furthermore, EP300 was indicated to activate DDR1 nor-NOHA acetate kinase rather than phosphorylation by TGF-β1 stimulation in MRC-5 lung fibroblasts. In summary, these results indicated EP300 as a potential therapeutic target of pulmonary fibrosis.
In the present study, we further discovered the synergistic inhibitory potency of EP300 and DDR1 in vitro and in vivo. EP300 inhibition only partially suppressed the activation of fibrotic cytokines, inflammation cytokines, and COL1 A1 stimulated by TGF-β1 in vitro and bleomycin in vivo. The DDR1 inhibitor CQ-061 displayed improved therapeutic effects than EP300 inhibition individually; however, significant synergistic effects were observed in DDR1 and EP300 inhibition. According to these results, we speculated that these synergistic effects may come from the DDR1 transcription activator capacity of EP300. Therefore, the synergistic effect of DDR1 and EP300 inhibition on pulmonary fibrosis was determined in vivo by using bleomycin-induced pulmonary murine models. Our results suggested that the inhibition of DDR1 or EP300 resulted in reduced fibrotic and inflammation cytokines and alleviated pulmonary fibrosis in vivo. In consideration of the complex functions of EP300 in different diseases, further studies are necessary to develop in-depth insights into the mechanisms of EP300 in pulmonary fibrosis. In any case, our bioinformatics and experimental results suggested that close links between EP300 and DDR1 may serve as therapeutic target pair in suppressing TGF-β1 signaling in pulmonary fibroblasts and bleomycin-induced murine models.
In general, these results suggested that EP300 and DDR1 synergistically acted as therapeutic regulators of TGF-β1 signaling in pulmonary fibrosis. Both EP300 and DDR1 expression were significantly up-regulated in IPF patients, and EP300 exerted potential fibrotic effects by activating DDR1 expression under TGF-β1 stimulation. Furthermore, pharmacological inhibition of EP300 by siRNA or inhibitors synergistically alleviated fibrotic and inflammation injury with DDR1 inhibitors in vitro and in vivo. Our results provide novel insights into the therapeutic potential of EP300 and DDR1 in the treatment of idiopathic pulmonary fibrosis or inflammatory pulmonary injury.
Funding source This study was supported by the National Natural Science Funds (NSFC 81573154 and 81773432), the Fundamental Research Funds of Science & Technology Department of Sichuan Province (2017JY0123), the China Postdoctoral Science Foundation (No. 2016M602696 and 2016M592679) and the open project of Chengdu University, Sichuan Industrial Institute of Antibiotics, Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province (ARRLKF17-02).
Introduction Vitiligo is an acquired, chronic depigmenting disorder of the skin characterized by gradual loss of melanocytes in depigmented areas of the skin. With a worldwide prevalence of 1%, vitiligo is considered to be the most common pigmentation disorder (Tarlé et al., 2014). Vitiligo is classified into two major forms, namely segmental and non-segmental vitiligo. The former is less common and usually occurs with a unilateral and band-shaped distribution. The latter characterized by symmetrical and bilateral white patches occurs with different clinical subtypes, including focal, acrofacial, vulgaris and universal (Ezzedine et al., 2015). Although the molecular basis is not known completely, the disappearance of melanocytes in vitiligo appears to involve with cell adhesion defects (Wagner et al., 2015). This theory has been supported by the weaker expression of two molecules identified in cell-cell adhesion, Epithelial Cadherin (E-cadherin) and Discoidin Domain Receptor Tyrosine kinase 1 (DDR1), in keratinocytes of depigmented vitiligo lesions compared to normal skin (Kim and Lee, 2010; Ricard et al., 2012).