MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents

Abstract

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 cancer͞testis 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 MageA2͞p53 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 A͞ET treatment in melanoma cells expressing high MAGE-A levels reestablishes p53 response and reverts the chemoresistance.

MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs

“…25 We have previously demonstrated that upon DNA damage MageA2 expression hampers the apoptotic response of cells by affecting p53 acetylation and transactivation function. 10 PMLIV is a known regulator of p53; indeed it has been shown that PMLIV by recruiting p53 to PML-NBs facilitates its acetylation inducing its transcriptional activity. 18,21 In this context, we asked whether MageA2 could also affect p53 acetylation as induced by PMLIV.…”

“…Thus, in human primary melanoma cells, MageA2 expression confers resistance to chemotherapeutic drugs by interfering with p53 acetylation, which can be reverted by HDAC inhibitor drugs. 10 Subsequently, other groups also described an opposite correlation between MAGE-A gene expression and p53 activity. 7,11,12 Interestingly, only MageA4 has been shown to be involved in some potentially anti-tumor functions such as gankyrin oncoprotein inhibition 13 and apoptosis induction.…”

HDAC3: taking the SMRT-N-CoRrect road to repression

“…These effects were thought to be mediated by regulation of p21 gene (Wilson et al, 2006). At a mechanistic level, HDAC3 was shown to be recruited by the tumor antigen MAGE-A to impair the transactivation of the tumor suppressor p53, thereby conferring chemoresistance (Monte et al, 2006). Finally, Narita et al (2005), based on studies with human maxillary carcinoma cells, proposed that inhibition of HDAC3 combined with hyperthermia may provide an efficient therapeutic approach for cancer.…”

L’intrusion des régulateurs de l’épigénome mâle dans les cellules somatiques cancéreuses

“…Des études supplémentaires ont montré que cette résistance à l'apoptose était associée à une action neutralisante des MAGE sur P53 [16]. En accord avec ces données, une autre étude a montré que MAGE-A2, un membre de la même famille, recrute l'histone-déacé-tylase 3 (HDAC3) et cible P53, et s'oppose ainsi à l'acétylation et à l'activation de P53 à la suite d'un traitement génotoxique [17]. De plus, MAGE-A1 recrute l'histone désacétylase HDAC1 et ainsi transforme le régulateur transcriptionnel SKIP en un répresseur de transcription [18].…”