The Transcription Factor GLI1 Mediates TGFb1 Driven EMT in Hepatocellular Carcinoma via a SNAI1-Dependent Mechanism

XIN ZHENG*; NATALIA B. RUMIE VITTAR*; XIAOHONG GAI; MAITE G. FERNANDEZ-BARRENA; CATHERINE D. MOSER; CHUNLING HU; LUCIANA L. ALMADA; ANGELA L. MCCLEARY-WHEELER; SHERINE F. ELSAWA; ANNE M. VRABEL; ABDIRASHID M. SHIRE; ANDREA COMBA; SNORRI S. THORGEIRSSON; YOUNGSOO KIM; QINGGUANG LIU; MARTIN E. FERNANDEZ-ZAPICO; LEWIS R. ROBERTS

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2012 vol. 7 p. 1 - 13

1932-6203

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-b1 (TGFb1) 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 TGFb1 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.