PLoS ONE (Jan 2012)

The transcription factor GLI1 mediates TGFβ1 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

DOI
https://doi.org/10.1371/journal.pone.0049581
Journal volume & issue
Vol. 7, no. 11
p. e49581

Abstract

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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.