Downregulation of the transcription factor GLI1 underlies the anti-tumoral properties of arachidonic acid

COMBA A; PASQUALINI ME; VARA MESSLER M; SILVA RA; FERNANDEZ- ZAPICO ME; EYNARD, ALDO R

BIOCHEMICAL JOURNAL

PORTLAND PRESS LTD

Lugar: Londres; Año: 2014

0264-6021

Numerous reports have demonstrated a tumor inhibitory effect of Polyunsaturated Fatty Acids (PUFAs). However, the molecular mechanisms modulating this phenomenon remain elusive. Here, we provide evidence of a novel anti-tumoral mechanism of the PUFA arachidonic acid (AA). In vivo and in vitro experiments showed that AA treatment decreases tumor growth and metastasis, and increases apoptosis. Molecular analysis of this effect showed reduced expression of a subset of anti-apoptotic proteins, including BCL-2, BFL-1/A1 and 4-1BB in AA-treated cells. AA significantly diminishes the expression and promoter activity of these molecules. We demonstrated that the downregulation of the oncogenic transcription factor GLI1 is the underlying mechanism controlling BCL-2, BFL-1/A1 and 4-1BB expression. Using luciferase reporter, chromatin immunoprecipitation, and expression studies, we demonstrate that GLI1 binds to the promoter of these antiapoptotic molecules, and increases their expression and promoter activity. Further characterization showed that AA regulates GLI1 expression through the modulation of its promoter via NFATc1-mediated silencing of this regulatory sequence. Finally, we provide evidence that the AA-induced apoptosis can be rescued by the reexpression of GLI1 in AA-sensitive cells. Collectively, these results define a novel mechanism underlying AA anti-tumoral functions that may serve as a foundation for the future PUFA-based therapeutic approaches.