MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents.
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 siRNA-mediated 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.
Monte
Martin
M
Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, Area Science Park, Padriciano 99, 34012 Trieste, Italy.
Simonatto
Marta
M
Peche
Leticia Y
LY
Bublik
Debora R
DR
Gobessi
Stefania
S
Pierotti
Marco A
MA
Rodolfo
Monica
M
Schneider
Claudio
C
D000951:Antigens, Neoplasm / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism; D058950:Melanoma-Specific Antigens / Q000096:biosynthesis* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000099186:Histone Deacetylase 3
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D000099186:Histone Deacetylase 3; C420909:Mage-a2 antigen; C574803:MageA2 protein, human; C012589:trichostatin A