Abstract
Endothelial–mesenchymal transition (EndMT) is a crucial phenomenon in regulating the development of diseases, including cancer metastasis and fibrotic disorders. The primary regulators of disease development are zinc-finger transcription factors belonging to the Snail family. In this study, we characterized the myocardin-related transcription factor (MRTF)-dependent mechanisms of a human snail promoter regulation in TGF-β-stimulated human endothelial cells. Although in silico analysis revealed that the snail promoter’s regulatory fragment contains one GCCG and two SP1 motifs that could be occupied by MRTFs, the genetic study confirmed that MRTF binds only to SP1 sites to promote snail expression. The more accurate studies revealed that MRTF-A binds to both SP1 elements, whereas MRTF-B to only one (SP1near). Although we found that each MRTF alone is capable of inducing snail expression, the direct cooperation of these proteins is required to reinforce snail expression and promote the late stages of EndMT within 48 hours. Furthermore, genetic and biochemical analysis revealed that MRTF-B alone could induce the late stage of EndMT. However, it requires a prolonged time. Therefore, we concluded that MRTFs might cause EndMT in a fast- and slow-dependent manner. Based on MRTF-dependent Snail upregulation, we recognized that TGF-β1, as an MRTF-B regulator, is involved in slow EndMT induction, whereas TGF-β2, which altered both MRTF-A and MRTF-B expression, promotes a fast EndMT process.
Highlights
Endothelial–mesenchymal transition (EndMT) is the process of cellular transdifferentiation regulated under both physiological and pathological conditions, such as fibrosis and cancer [1]
We previously observed that myocardin-related transcription factor (MRTF)-A and MRTF-B are involved in the regulation of EndMT in HMEC-1 cells
We revealed that MRTF-A or MRTF-B overexpression resulted in a significant increase in Snail protein, with 3.7- and 4.6-fold increases, respectively, in HMEC-1, and 2.6- and 2.4-fold increases, respectively, in HUVECs (Figure 3C)
Summary
Endothelial–mesenchymal transition (EndMT) is the process of cellular transdifferentiation regulated under both physiological and pathological conditions, such as fibrosis and cancer [1]. EndMT is primarily induced by tumor growth factor-β family proteins (TGF-β) [10] through Smad-dependent and Smad-independent pathways (via the Rho family of GTPases) [11,12,13]. EndMT results in the impairment of the cell–cell junction and a spindle-like morphology manifested as increased cell migration and cell contraction abilities. These alterations are accompanied by a loss of endothelial markers expression and the gain of mesenchymal markers [14]. EndMT is correlated with an increased expression of specific zinc-finger transcription factors, such as Snail and Slug [14,15,16,17,18]; their regulation is cell-type dependent
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