TY - JOUR
T1 - The Transcription Factor GLI1 Mediates TGFβ1 Driven EMT in Hepatocellular Carcinoma via a SNAI1-Dependent Mechanism
AU - Zheng, Xin
AU - Rumie Vittar, Natalia B.
AU - Gai, Xiaohong
AU - Fernandez-Barrena, Maite G.
AU - Moser, Catherine D.
AU - Hu, Chunling
AU - Almada, Luciana L.
AU - McCleary-Wheeler, Angela L.
AU - Elsawa, Sherine F.
AU - Vrabel, Anne M.
AU - Shire, Abdirashid M.
AU - Comba, Andrea
AU - Thorgeirsson, Snorri S.
AU - Kim, Youngsoo
AU - Liu, Qingguang
AU - Fernandez-Zapico, Martin E.
AU - Roberts, Lewis R.
PY - 2012/11/19
Y1 - 2012/11/19
N2 - The role of the epithelial-to-mesenchymal transition (EMT) during hepatocellular carcinoma (HCC) progression is well established, however the regulatory mechanisms modulating this phenomenon remain unclear. Here, we demonstrate that transcription factor glioma-associated oncogene 1 (GLI1) modulates EMT through direct up-regulation of SNAI1 and serves as a downstream effector of the transforming growth factor-β1 (TGFβ1) pathway, a well-known regulator of EMT in cancer cells. Overexpression of GLI1 increased proliferation, viability, migration, invasion, and colony formation by HCC cells. Conversely, GLI1 knockdown led to a decrease in all the above-mentioned cancer-associated phenotypes in HCC cells. Further analysis of GLI1 regulated cellular functions showed that this transcription factor is able to induce EMT and identified SNAI1 as a transcriptional target of GLI1 mediating this cellular effect in HCC cells. Moreover, we demonstrated that an intact GLI1-SNAI1 axis is required by TGFβ1 to induce EMT in these cells. Together, these findings define a novel cellular mechanism regulated by GLI1, which controls the growth and EMT phenotype in HCC.
AB - The role of the epithelial-to-mesenchymal transition (EMT) during hepatocellular carcinoma (HCC) progression is well established, however the regulatory mechanisms modulating this phenomenon remain unclear. Here, we demonstrate that transcription factor glioma-associated oncogene 1 (GLI1) modulates EMT through direct up-regulation of SNAI1 and serves as a downstream effector of the transforming growth factor-β1 (TGFβ1) pathway, a well-known regulator of EMT in cancer cells. Overexpression of GLI1 increased proliferation, viability, migration, invasion, and colony formation by HCC cells. Conversely, GLI1 knockdown led to a decrease in all the above-mentioned cancer-associated phenotypes in HCC cells. Further analysis of GLI1 regulated cellular functions showed that this transcription factor is able to induce EMT and identified SNAI1 as a transcriptional target of GLI1 mediating this cellular effect in HCC cells. Moreover, we demonstrated that an intact GLI1-SNAI1 axis is required by TGFβ1 to induce EMT in these cells. Together, these findings define a novel cellular mechanism regulated by GLI1, which controls the growth and EMT phenotype in HCC.
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U2 - 10.1371/journal.pone.0049581
DO - 10.1371/journal.pone.0049581
M3 - Article
C2 - 23185371
AN - SCOPUS:84869782914
SN - 1932-6203
VL - 7
JO - PloS one
JF - PloS one
IS - 11
M1 - e49581
ER -