Hyperacetylation enhances the growth-inhibitory effect of all-trans retinoic acid by the restoration of retinoic acid receptor beta expression in head and neck squamous carcinoma (HNSCC) cells

초록

The chemotherapeutic effects of all-trans-retinoic acid (atRA) are mediated by the retinoic acid receptor beta (RAR beta), but RAR beta expression is reduced in a number of head and neck carcinoma (HNSCC) cells which causes resistance to RA treatment in half the patients with HNSCC. The possible mechanism for the reduced RAR beta expression has been suggested as the methylation of the CpG islands adjacent to the RA response elements (RARE) in the RAR beta promoter and the loss of histone acetylation. The suppressed RAR beta expression can be reactivated by a demethylating agent (5-aza-2'-deoxycytidine, 5-AzaC) or a histone deacetylase inhibitor (trichostatin A, TSA). Therefore, we sought to determine if the restoration of RAR beta activity, or a combination of these drugs, could restore the sensitivity to RA in RAR beta-negative HNSCC cells with an epigenetically methylated RAR beta promoter region. SqCC/Y1 cells resistant to atRA showed methylated and unmethylated forms in the RAR beta promoter region. RAR beta expression of these cells was restored by 5-AzaC or TSA treatment. Also, treatment with TSA and atRA combined synergistically increased the growth-inhibitory effect and highly induced the transcriptional activation of the RAR beta promoter compared to atRA treatment in HNSCC cells. Additionally, TSA alone and the combination 5-AzaC and TSA increased lysine-9 (Lys-9) acetylation and Lys-4 methylation of the first exon at the RAR beta gene, while decreasing the methylation of Lys-9 in the HNSCC cells.

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