Abstract
The cytokine transforming growth factor β (TGFβ) plays a crucial role in the induction of both epithelial-to-mesenchymal transition (EMT) program and fibro-cirrhotic process in the liver, where it contributes also to organ inflammation following several chronic injuries. All these pathological situations greatly increase the risk of hepatocellular carcinoma (HCC) and contribute to tumor progression. In particular, late-stage HCCs are characterized by constitutive activation of TGFβ pathway and by an EMT molecular signature leading to the acquisition of invasive and metastatic properties. In these pathological conditions, the cytokine has been shown to induce the transcriptional downregulation of HNF1α, a master regulator of the epithelial/hepatocyte differentiation and of the EMT reverse process, the mesenchymal-to-epithelial transition (MET). Therefore, the restoration of HNF1α expression/activity has been proposed as targeted therapeutic strategy for liver fibro-cirrhosis and late-stage HCCs. In this study, TGFβ is found to trigger an early functional inactivation of HNF1α during EMT process that anticipates the effects of the transcriptional downregulation of its own gene. Mechanistically, the cytokine, while not affecting the HNF1α DNA-binding capacity, impaired its ability to recruit CBP/p300 acetyltransferases on target gene promoters and, consequently, its transactivating function. The loss of HNF1α capacity to bind to CBP/p300 and HNF1α functional inactivation have been found to correlate with a change of its posttranslational modification profile. Collectively, the results obtained in this work unveil a new level of HNF1α functional inactivation by TGFβ and contribute to shed light on the early events triggering EMT in hepatocytes. Moreover, these data suggest that the use of HNF1α as anti-EMT tool in a TGFβ-containing microenvironment may require the design of new therapeutic strategies overcoming the TGFβ-induced HNF1α inactivation.
Highlights
Transforming growth factor β (TGFβ) has emerged as a major microenvironmental factor playing a role in all phases of chronic liver diseases (Fabregat et al, 2016)
In order to verify the possibility to use alternatively HNF1α as mesenchymal-to-epithelial transition (MET) inducer in a transforming growth factor β (TGFβ)-rich microenvironment, we explored the effect of this cytokine on the HNF1α protein function
The first evidence of an additional level of HNF1α negative control induced by TGFβ came from a time course analysis of HNF1α-dependent gene expression regulation in hepatocytes treated with the cytokine
Summary
Transforming growth factor β (TGFβ) has emerged as a major microenvironmental factor playing a role in all phases of chronic liver diseases (Fabregat et al, 2016). This cytokine, is primarily involved in liver inflammation (by stimulating lymphocytes to produce inflammatory cytokines), in fibrosis (by activating the trans-differentiation of hepatic stellate cells to myofibroblasts and the subsequent production of large amount of extracellular matrix), and in the onset of hepatocellular carcinoma (HCC) that, in almost all the cases, develops on the described pathological tissue background (Amicone and Marchetti, 2018). The cytokine induces the transdifferentiation process through the upregulation of EMT/ mesenchymal genes (Xu et al, 2009) and the strong transcriptional downregulation of master regulators of epithelial/hepatocyte differentiation, such as HNF4α and HNF1α (Marchetti et al, 2013)
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