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 language | English |
|---|---|
| Pages (from-to) | 543-555 |
| Number of pages | 13 |
| Journal | Cancer Chemotherapy and Pharmacology |
| Volume | 56 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2005 Nov 1 |
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Keywords
- Growth-inhibitory effect
- HNSCC
- Hyperacetylation
- Retinoic acid receptor
ASJC Scopus subject areas
- Cancer Research
- Pharmacology
- Oncology
Cite this
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. / Whang, Young Mi; Choi, Eun Jung; Seo, Jae Hong; Kim, Jun Suk; Yoo, Young Do; Kim, Yeul Hong.
In: Cancer Chemotherapy and Pharmacology, Vol. 56, No. 5, 01.11.2005, p. 543-555.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Whang, Young Mi
AU - Choi, Eun Jung
AU - Seo, Jae Hong
AU - Kim, Jun Suk
AU - Yoo, Young Do
AU - Kim, Yeul Hong
PY - 2005/11/1
Y1 - 2005/11/1
N2 - 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.
AB - 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.
KW - Growth-inhibitory effect
KW - HNSCC
KW - Hyperacetylation
KW - Retinoic acid receptor
UR - http://www.scopus.com/inward/record.url?scp=27644528863&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=27644528863&partnerID=8YFLogxK
U2 - 10.1007/s00280-004-0970-3
DO - 10.1007/s00280-004-0970-3
M3 - Article
C2 - 15959780
AN - SCOPUS:27644528863
VL - 56
SP - 543
EP - 555
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 5
ER -