Induction of GADD45α expression contributes to the anti-proliferative effects of polymethoxyflavones on colorectal cancer cells

Polymethoxyflavones (PMFs), such as nobiletin and tangeretin, have a high cellular uptake rate, on account of their hydrophobicity. Nobiletin has been shown to down-regulate inflammatory gene expression, and is thus considered a promising anti-inflammatory and anti-carcinogenic agent. Most proteins known to be affected by PMFs are cell cycle regulators and kinases. In the present study, we demonstrate that PMF-mediated induction of GADD45α partially underlies the anti-proliferative effect of PMF on colorectal cancer cells. PMF-mediated induction of GADD45α was found to be associated with chromatin remodeling events at a novel enhancer element residing at intron 1 of GADD45α. Moreover, GADD45α transcription correlated with differential acetylation of lysines 14 and 27 of histone H3 (H3K14/27) following treatment with either nobiletin or tangeretin. PMF-induced changes in H3K27 acetylation, H2A.Z and CBP were observed at intron 1, but not at p53 response-elements of GADD45α, suggesting that nobiletin/tangeretin-mediated GADD45α activation may be independent of p53.