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

Young Mi Whang, Eun Jung Choi, Jae Hong Seo, Jun Suk Kim, Young Do Yoo, Yeul Hong Kim

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The chemotherapeutic effects of all-trans-retinoic acid (atRA) are mediated by the retinoic acid receptor β (RARβ), but RARβ 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 RARβ expression has been suggested as the methylation of the CpG islands adjacent to the RA response elements (RARE) in the RARβ promoter and the loss of histone acetylation. The suppressed RARβ 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 RARβ activity, or a combination of these drugs, could restore the sensitivity to RA in RARβ-negative HNSCC cells with an epigenetically methylated RARβ promoter region. SqCC/Y1 cells resistant to atRA showed methylated and unmethylated forms in the RARβ promoter region. RARβ 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 RARβ 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 RARβ gene, while decreasing the methylation of Lys-9 in the HNSCC cells.

Original languageEnglish
Pages (from-to)543-555
Number of pages13
JournalCancer Chemotherapy and Pharmacology
Volume56
Issue number5
DOIs
Publication statusPublished - 2005 Nov

Keywords

  • Growth-inhibitory effect
  • HNSCC
  • Hyperacetylation
  • Retinoic acid receptor

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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