title: 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.
abstract: The chemotherapeutic effects of all-trans-retinoic acid (atRA) are mediated by the retinoic acid receptor beta (RARbeta), but RARbeta 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 RARbeta expression has been suggested as the methylation of the CpG islands adjacent to the RA response elements (RARE) in the RARbeta promoter and the loss of histone acetylation. The suppressed RARbeta 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 RARbeta activity, or a combination of these drugs, could restore the sensitivity to RA in RARbeta-negative HNSCC cells with an epigenetically methylated RARbeta promoter region. SqCC/Y1 cells resistant to atRA showed methylated and unmethylated forms in the RARbeta promoter region. RARbeta 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 RARbeta 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 RARbeta gene, while decreasing the methylation of Lys-9 in the HNSCC cells.
authors.affiliation: Department of Internal Medicine and Brain Korea 21 Program for Biomedical Sciences, Korea University College of Medicine, Seongbuk-Gu, Seoul.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Whang
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Choi
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seo
authors.forename: Jun Suk
authors.initials: JS
authors.lastname: Kim
authors.forename: Young Do
authors.initials: YD
authors.lastname: Yoo
authors.forename: Yeul Hong
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006258:Head and Neck Neoplasms; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008239:Lysine / Q000737:chemistry; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; C012589:trichostatin A; D014212:Tretinoin; D000077209:Decitabine; D008239:Lysine; D001374:Azacitidine