These three authors contributed equally to the work.
GLI2 and M-MITF transcription factors control exclusive gene expression programs and inversely regulate invasion in human melanoma cells
Article first published online: 18 AUG 2011
© 2011 John Wiley & Sons A/S
Pigment Cell & Melanoma Research
Volume 24, Issue 5, pages 932–943, October 2011
How to Cite
Javelaud, D., Alexaki, V.-I., Pierrat, M.-J., Hoek, K. S., Dennler, S., Van Kempen, L., Bertolotto, C., Ballotti, R., Saule, S., Delmas, V. and Mauviel, A. (2011), GLI2 and M-MITF transcription factors control exclusive gene expression programs and inversely regulate invasion in human melanoma cells. Pigment Cell & Melanoma Research, 24: 932–943. doi: 10.1111/j.1755-148X.2011.00893.x
- Issue published online: 10 OCT 2011
- Article first published online: 18 AUG 2011
- Accepted manuscript online: 1 AUG 2011 04:21AM EST
- PUBLICATION DATA Received 15 November 2010, revised and accepted for publication 27 July 2011, published online 1 August 2011
- Protein kinase A;
- gene knock-down
We recently identified GLI2, the most active of GLI transcription factors, as a direct TGF-β/SMAD target, whose expression in melanoma cells is associated with increased invasiveness and metastatic capacity. In this work, we provide evidence that high GLI2 expression is inversely correlated with that of the melanocyte-specific transcription factor M-microphthalmia transcription factor (M-MITF) and associated transcriptional program. GLI2-expressing cell lines were characterized by the loss of M-MITF-dependent melanocytic differentiation markers and reduced pigmentation. The balance between M-MITF and GLI2 expression did not correlate with the presence or absence of BRAF-activating mutations, but rather was controlled by two distinct pathways: the TGF-β pathway, which favors GLI2 expression, and the protein kinase A (PKA)/cAMP pathway, which pushes the balance toward high M-MITF expression. Furthermore, overexpression and knockdown experiments demonstrated that GLI2 and M-MITF reciprocally repress each other’s expression and control melanoma cell invasion in an opposite manner. These findings thus identify GLI2 as a critical transcription factor antagonizing M-MITF function to promote melanoma cell phenotypic plasticity and invasive behavior.