Transforming growth factor-β (TGF-β) is an inducer of
type I collagen, and uncontrolled
collagen production leads to tissue
scarring and organ failure. Here we hypothesize that uncovering a molecular mechanism that enables us to switch off
type I collagen may prove beneficial in treating
fibrosis. For the first time, to our knowledge, we provide evidence that CUX1 acts as a negative regulator of TGF-β and potent inhibitor of
type I collagen transcription. We show that CUX1, a CCAAT displacement
protein, is associated with reduced expression of
type I collagen both in vivo and in vitro. We show that enhancing the expression of CUX1 results in effective suppression of
type I collagen. We demonstrate that the mechanism by which CUX1 suppresses
type I collagen is through interfering with gene transcription. In addition, using an in vivo murine model of
aristolochic acid (AA)-induced interstitial
fibrosis and human AA nephropathy, we observe that CUX1 expression was significantly reduced in fibrotic tissue when compared to control samples. Moreover, silencing of CUX1 in fibroblasts from kidneys of patients with renal
fibrosis resulted in increased
type I collagen expression. Furthermore, the abnormal CUX1 expression was restored by addition of TGF-β via the
p38 mitogen-activated protein kinase pathway. Collectively, our study demonstrates that modifications of CUX1 expression lead to aberrant expression of
type I collagen, which may provide a molecular basis for fibrogenesis.