Histone deacetylase inhibitors upregulate Rap1GAP and inhibit Rap activity in thyroid tumor cells.
Endocr Relat Cancer
; 18(3): 301-10, 2011 Jun.
Article
em En
| MEDLINE
| ID: mdl-21367844
ABSTRACT
Increases in Rap activity have been associated with tumor progression. Although activating mutations in Rap have not been described, downregulation of Rap1GAP is frequent in human tumors including thyroid carcinomas. In this study, we explored whether endogenous Rap1GAP expression could be restored to thyroid tumor cells. The effects of deacetylase inhibitors and a demethylating agent, individually and in combination, were examined in four differentiated and six anaplastic thyroid carcinoma (ATC) cell lines. Treatment with the structurally distinct histone deacetylase (HDAC) inhibitors, sodium butyrate and trichostatin A, increased Rap1GAP expression in all the differentiated thyroid carcinoma cell lines and in four of the six ATC cell lines. The demethylating agent, 5-aza-deoxycytidine, restored Rap1GAP expression in one anaplastic cell line and enhanced the effects of HDAC inhibitors in a second anaplastic cell line. Western blotting indicated that Rap2 was highly expressed in human thyroid cancer cells. Importantly, treatment with HDAC inhibitors impaired Rap2 activity in both differentiated and anaplastic tumor cell lines. The mechanism through which Rap activity is repressed appears to entail effects on the expression of multiple Rap regulators, including RapGEFs and RapGAPs. These results suggest that HDAC inhibitors may provide a tractable approach to impair Rap activity in human tumor cells.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Butiratos
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Neoplasias da Glândula Tireoide
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Carcinoma
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Regulação Neoplásica da Expressão Gênica
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Proteínas rap de Ligação ao GTP
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Proteínas rap1 de Ligação ao GTP
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Proteínas Ativadoras de GTPase
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Inibidores de Histona Desacetilases
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Ácidos Hidroxâmicos
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Proteínas de Neoplasias
Limite:
Humans
Idioma:
En
Revista:
Endocr Relat Cancer
Ano de publicação:
2011
Tipo de documento:
Article