TGF-β–induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis

Cellular and molecular mechanisms in fibrosis

“…The expression of both DNMTs was also upregulated in skin and fibroblasts isolated from SSc patients. [136] The study further demonstrated that the TGF-β-induced silencing of SOCS3 amplified signalling through JAK2 and STAT3 with increased levels of phosphorylated STAT3, thereby again underlining the importance of signalling crosstalk between different profibrotic pathways. [136] TGF-β-induced DNMT expression also promotes activation of the canonical WNT pathway by silencing of the endogenous WNT antagonists DKK1 and SFRP1.…”

“…[136] The study further demonstrated that the TGF-β-induced silencing of SOCS3 amplified signalling through JAK2 and STAT3 with increased levels of phosphorylated STAT3, thereby again underlining the importance of signalling crosstalk between different profibrotic pathways. [136] TGF-β-induced DNMT expression also promotes activation of the canonical WNT pathway by silencing of the endogenous WNT antagonists DKK1 and SFRP1. [69] Treatment with the DNMT inhibitor 5-aza-2'-deoxycytidine (Decitabine) has consistently been shown to exert antifibrotic effects in experimental models of dermal and pulmonary fibrosis.…”

“…Several studies have implicated DNA methylation-induced silencing of antifibrotic genes in the pathogenesis of fibrotic tissue remodelling. [69,[136][137][138][139] The best-studied target of DNA methylation in SSc is…”

“…[138,142] A recent study showed that persistently increased levels of TGF-β suppressed the expression of suppressor of cytokine signalling 3 (SOCS3) by inducing hypermethylation of its promoter. [136] Mechanistically, TGF-β induced both the activity and the expression of DNMT1 and DNMT3A in dermal fibroblasts. The expression of both DNMTs was also upregulated in skin and fibroblasts isolated from SSc patients.…”

“…[69] Treatment with the DNMT inhibitor 5-aza-2'-deoxycytidine (Decitabine) has consistently been shown to exert antifibrotic effects in experimental models of dermal and pulmonary fibrosis. [69,136,143]…”