Emerging role of Twist1 in fibrotic diseases - PubMed (original) (raw)

The role and mechanism of Twist1 in renal, pulmonary and skin fibrosis. (A) The role and mechanism of Twist1 in renal fibrosis. Hypoxia induces the expression of

HIF

‐1α that can bind to the proximal

HRE

of Twist1 at ‐317 to ‐312 in tubular epithelial cells and modulate Twist1 expression. Moreover, Twist1 and

HIF

‐1α can bind to Bmi1 promoter at ‐732 to ‐727 and ‐190 to ‐185, respectively, and cooperatively promote Bmi1 expression. Bmi1 induces the

EMT

program via activation of

3K/Akt signalling to increase

ECM

deposition, resulting in renal fibrosis. The Wnt/β‐catenin pathway can also increase Twist1 expression, leading to renal fibrosis. However, direct interaction between Notch or Hedgehog signalling and Twist1 expression has not been found in renal fibrosis, and the hypothesis needs further investigation. (B) The role and mechanism of Twist1 in pulmonary fibrosis. In alveolar epithelial cells, persistent hypoxia induces

HIF

‐1α expression and de novo Twist1 expression, leading to repression of

‐D that can inhibit the

EMT

process. Twist1 also promotes the

EMT

process directly, resulting in the accumulation of

ECM

and pulmonary fibrosis. Bleomycin‐induced lung fibrosis via the activation of

TGF

‐β1 signalling and up‐regulation of Twist1 could be ameliorated by drugs like

ATRA

and methacycline that could block

TGF

‐β1 signalling. Bleomycin‐stimulated Twist1 Ser42 phosphorylation controls angiogenesis via activating Tie2 signalling. Id2 could promote the proliferation of primary alveolar epithelial cells and block

TGF

‐β1‐stimulated type I collagen expression by inhibiting Twist1.

BRD

4 binds to phospho‐Ser276

‐κB/RelA stimulated by

TGF

‐β1 to regulate the expression of

EMT

regulators including Twist1. Moreover, Twist1 could protect lung fibroblasts from apoptosis stimulated by growth factor partly by negatively regulating the expression of Bim and

PUMA

. In addition, loss of Twist1 in collagen‐producing cells augments bleomycin‐induced experimental pulmonary fibrosis that is associated with the elevated expression of non‐canonical

‐κB transcription factor RelB and T‐cell chemoattractant

CXCL

12, which causes the accumulation of T cells. (C) The role and mechanism of Twist1 in skin fibrosis. Twist1 expression is elevated in fibroblasts of fibrotic skin in a

TGF

‐β/Smad3/p38‐dependent manner. In turn, the enhanced Twist1 promotes the activation of the p38 pathway. In addition to promoting Twist1 expression,

TGF

‐β also induces the up‐regulation of

proteins, which have high affinity for E12/E47 and compete with Twist1 for binding E12/E47 proteins. This situation leads to the formation of Twist1 homodimers that can promote the expression of type I collagen via direct binding to the promoters of

COL

1A1 and

COL

1A2. Additionally, Twist1 can promote End

, which is responsible for skin fibrosis.