The CBX7 protein, whose expression is decreased in human carcinomas, positively regulates E-cadherin expression by interacting with the HDAC2 protein.
Bianco, Mimma (2009) The CBX7 protein, whose expression is decreased in human carcinomas, positively regulates E-cadherin expression by interacting with the HDAC2 protein. [Tesi di dottorato] (Inedito)
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CBX7, chromobox homolog 7, is a chromobox family protein encoding a novel Polycomb protein, component of the Polycomb repressive complex 1 (PRC1). The Polycomb group (PcG) proteins are epigenetic transcriptional repressors involved in the control of cellular proliferation and oncogenesis. CBX7 protein levels show a progressive reduction, well related with the malignant grade of the thyroid neoplasias. Indeed, its expression decreased in an increasing percentage of cases going from benign adenomas to papillary, follicular and anaplastic thyroid carcinomas. To elucidate the function of CBX7 in carcinogenesis, we searched for CBX7 interacting proteins by a proteomic analysis. By this approach, we identified several proteins among which we selected Histone Deacetylase 2 (HDAC2) that is well known to play a key role in neoplastic cell transformation and to downregulate E-cadherin expression, whose loss is a critical event in the Epithelial-Mesenchymal Transition, and therefore emerging as one of the caretakers of the epithelial phenotype. We confirmed by co-immunoprecipitation that CBX7 physically interacts with the HDAC2 and demostrated that is able to inhibit its activity. Then, we showed that both these proteins bind the E-cadherin promoter, and that CBX7 is able to upregulate E-cadherin expression. Consistent with these data we found a positive statistical correlation between CBX7 and E-cadherin expression in human thyroid carcinomas. Finally, we demonstrated that the expression of CBX7 increases the acetylation status of the histones H3 and H4 on the E-cadherin promoter. Therefore, the ability of CBX7 to positively regulate E-cadherin expression, by interacting with HDAC2 and inhibiting its activity on the E-cadherin promoter, would account for the correlation between the loss of CBX7 expression and a highly malignant phenotype in thyroid cancer patients. Thus, several important interacting proteins of CBX7 and the pathways in which they are involved strongly suggest that CBX7 can be considerated a very important regulator of thyroid malignant transformation.
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