MAGE-A Tumor Antigens Target p53 Transactivation Function through Histone Deacetylase Recruitment and Confer Resistance to Chemotherapeutic Agents

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 30; pp. 11160 - 11165
• Main Authors: Monte, Martin, Simonatto, Marta, Peche, Leticia Y., Bublik, Debora R., Gobessi, Stefania, Pierotti, Marco A., Rodolfo, Monica, Schneider, Claudio
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.07.2006; National Acad Sciences
• Subjects: Acetylation; Antigens; Antigens, Neoplasm - physiology; Antineoplastic Agents - pharmacology; Apoptosis; Biological Sciences; Cell Line, Tumor; Cell lines; Chemotherapy; DNA Damage; Drug Resistance, Neoplasm; Gene expression; Gene Expression Regulation, Neoplastic; Histone Deacetylases - chemistry; Histone Deacetylases - metabolism; Histones; Humans; Hydroxamic Acids - pharmacology; Initial value theorem; Melanoma; Melanoma - metabolism; Melanoma-Specific Antigens - biosynthesis; Melanoma-Specific Antigens - metabolism; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - metabolism; Polymerase chain reaction; Protein Structure, Tertiary; Proteins; Small interfering RNA; Transcriptional Activation; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0510834103

The MAGE gene family is characterized by a conserved domain (MAGE Homology Domain). A subset of highly homologous MAGE genes (group A; MAGE-A) belong to the chromosome X-clustered cancer/testis antigens. MAGE-A genes are normally expressed in the human germ line and overexpressed in various tumor types; however, their biological function is largely unknown. Here we present evidence indicating that MageA2 protein, belonging to the MAGE-A subfamily, confers wild-type-p53-sensitive resistance to etoposide (ET) by inducing a novel p53 inhibitory loop involving recruitment of histone deacetylase 3 (HDAC3) to MageA2/p53 complex, thus strongly down-regulating p53 transactivation function. In fact, enhanced MageA2 protein levels, in addition to ET resistance, correlate with impaired acetylation of both p53 and histones surrounding p53-binding sites. Association between MAGE-A expression levels and resistance to ET treatment is clearly shown in short-term cell lines obtained from melanoma biopsies harboring wild-type-p53, whereas cells naturally, or siRNAmediated expressing low MAGE-A levels, correlate with enhanced p53-dependent sensitivity to ET. In addition, combined trichostatin A/ET treatment in melanoma cells expressing high MAGE-A levels reestablishes p53 response and reverts the chemoresistance.