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Chromobox Protein Homologue 7 Protein, with Decreased Expression in Human Carcinomas, Positively Regulates E-Cadherin Expression by Interacting with the Histone Deacetylase 2 Protein

¹ Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare and ² Dipartimento di Anatomia Patologica e Citopatologia, Facoltà di Medicina e Chirurgia di Napoli, Università degli studi di Napoli "Federico II"; ³ Naples Oncogenomic Center-CEINGE, Biotecnologie Avanzate-Napoli, and European School of Molecular Medicine-Naples Site; ⁴ CEINGE, Biotecnologie Avanzate-Napoli and Dipartimento di Chimica Organica e Biochimica, Università degli studi di Napoli "Federico II," Naples, Italy

Requests for reprints: Alfredo Fusco, Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, via Pansini 5, 80131 Napoli, Italy. Phone: 39-81-7463602; Fax: 39-81-2296674; E-mail: afusco{at}napoli.com or alfusco{at}unina.it.

Key Words: CBX7 • E-cadherin • HDAC2

Chromobox protein homologue 7 (CBX7) is a chromobox family protein encoding a novel polycomb protein, the expression of which shows a progressive reduction, well related with the malignant grade of the thyroid neoplasias. Indeed, CBX7 protein levels 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 these proteins, we selected histone deacetylase 2 (HDAC2), which is well known to play a key role in neoplastic cell transformation and down-regulation of E-cadherin expression, the loss of which is a critical event in the epithelial-to-mesenchymal transition. We confirmed by coimmunoprecipitation that CBX7 physically interacts with the HDAC2 protein and is able to inhibit its activity. Then, we showed that both these proteins bind the E-cadherin promoter and that CBX7 up-regulates 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 showed 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. [Cancer Res 2009;69(17):7079–87]