EZH2 is involved in psoriasis progression by impairing miR-125a-5p inhibition of SFMBT1 and leading to inhibition of the TGFβ/SMAD pathway

Abstract

Aims: In this study, we aimed to decipher the impact of enhancer of zeste homolog 2 (EZH2) in psoriasis as well as the underlying mechanism. Methods: A mouse model of psoriasis was developed by means of imiquimod induction, with the expression of EZH2, microRNA-125a-5p (miR-125a-5p), and SFMBT1 determined. The role of EZH2, miR-125a-5p, and SFMBT1 in malignant phenotypes of HaCaT cells and the development of psoriasis in vivo was subsequently investigated through gain- and loss-of-function experiments. Chromatin immunoprecipitation assay and dual-luciferase reporter assay were conducted to explore the relationship between EZH2 or SFMBT1 and miR-125a-5p. Finally, the effects of EZH2 and miR-125a-5p on the transforming growth factor β (TGFβ)/SMAD pathway were analyzed. Results: Overexpressed SFMBT1 and EZH2 was detected while miR-125a-5p were downregulated in psoriasis tissues and human keratinocyte (HaCaT) cells. EZH2 increased the levels of IL-17A-induced cytokines and promoted the malignant phenotypes of HaCaT cells. Functionally, EZH2 reduced miR-125a-5p expression while miR-125a-5p targeted SFMBT1 to activate the TGFβ/SMAD pathway in vitro. Knockdown of EZH2 or up-regulation of miR-125a-5p inhibited cell proliferation and the levels of IL-17A-induced cytokines, but increased the expression of TGFβ1 and the extent of smad2 and smad3 phosphorylation in HaCaT cells. Notably, EZH2 contributed to the development of psoriasis in vivo by inhibiting the TGFβ/SMAD pathway via impairment of miR-125a-5p-mediated SFMBT1 inhibition. Conclusion: Taken together, the results of the current study highlight the ability of EZH2 to potentially inactivate the TGFβ/SMAD pathway via upregulation of miR-125a-5p-dependent SFMBT1during the progression of psoriatic lesions.

Serum miRNA profiling identified miRNAs associated with disease severity in psoriasis

“…46 In psoriasis, hypermethylation of miR-125a-5p promoter by enhancer of zeste homologue 2 (EZH2) downregulates the miRNA expression, which in turn results in upregulation of IL17a-induced cytokines. 47 MiR-147b showed nearly 85% accuracy in detecting low severity psoriasis patients from normal, whereas miR-3614-5p and miR-125a-5p showed an accuracy >90%…”

“…MiR‐125a is reportedly downregulated in CD4 + T cells in various autoimmune diseases like systemic lupus erythematosus (SLE) and Crohn's disease, and reduced level of miR‐125a leads to upregulation of several effector T cell factors including Signal transducer and activator of transcription 3 (STAT3), Interferon gamma (IFNg) 46 . In psoriasis, hypermethylation of miR‐125a‐5p promoter by enhancer of zeste homologue 2 (EZH2) downregulates the miRNA expression, which in turn results in upregulation of IL17a‐induced cytokines 47 . MiR‐147b showed nearly 85% accuracy in detecting low severity psoriasis patients from normal, whereas miR‐3614‐5p and miR‐125a‐5p showed an accuracy >90% for moderate to high severity patients (Figure S3b–d).…”

Genetic and Epigenetic Mechanisms of Psoriasis

“…However, many other dysregulated miRNAs, have been shown to be involved in psoriasis pathogenesis, modulating the immune response and skin inflammation as well as epithelial differentiation and proliferation [ 76 ]. Among them, miR-230 [ 77 ], mir-383 [ 78 ], Mir-214-3p [ 79 ], or miR-125a-5p [ 80 ] are downregulated; whereas, miR-378a [ 81 ], Mir-31 [ 82 ], mir-210 [ 83 ], miR-200c [ 84 ], or miR-155 [ 85 ] are upregulated in psoriasis.…”

Gene Set Enrichment Analysis and Ingenuity Pathway Analysis to verify the impact on Wnt Signaling Pathway in Taodan Granules Treated Psoriasis

“…In vivo, GSK126, the inhibitor of EZH2, GSK126 can ameliorate the IMQ-induced psoriatic lesions. EZH2 contributes to the development of psoriasis by inhibiting the transforming growth factor-β (TGFβ)/recombinant mothers against decapentaplegic homolog (SMAD) pathway impairment of miR-125a-5p-mediated Sex comb on midleg with four malignant brain tumor domains (SFMBT) 1 inhibition [43][44][45]. CTNNB1 gene is located on chromosome 3p21, and the mutation of the gene exon 3 causes nuclear accumulation of β-catenin.…”