Epigenetic regulation of MAGE family in human cancer progression-DNA methylation, histone modification, and non-coding RNAs

Abstract

The melanoma antigen gene (MAGE) proteins are a group of highly conserved family members that contain a common MAGE homology domain. Type I MAGEs are relevant cancer-testis antigens (CTAs), and originally considered as attractive targets for cancer immunotherapy due to their typically high expression in tumor tissues but restricted expression in normal adult tissues. Here, we reviewed the recent discoveries and ideas that illustrate the biological functions of MAGE family in cancer progression. Furthermore, we also highlighted the current understanding of the epigenetic mechanism of MAGE family expression in human cancers.

Keywords: E3 RING ubiquitin ligases; Epigenetics; MAGE; Transcription regulator.

Fig. 1

MAGEs function as regulator of E3 RING ubiquitin ligases. MAGE genes were activated by some epigenetic regulation factors such as DNA demethylation, histone acetylation, decreased nucleosome occupancy, and altered expression of non-coding RNAs. Then they were translated to proteins which could bind directly to RING domain proteins and act as scaffold of RING domain proteins to their substrates, thus regulating (increase or decrease) the ubiquitin ligase activity of RING domain proteins, which plays an important role in tumor development.

Fig. 2

MAGEs function as transcription regulators. (1). MAGEs regulate KAP1 activity as transcription activator. a KAP1 functions as a molecular scaffold for gene-specific silencing by targeting of specific promoters through the KRAB protein zinc finger motifs, promotion of histone deacetylation via the NuRD/histone deacetylase complex, histone H3-K9 methylation via SETDB1 and recruitment of HP1 protein. b MAGE-C2 binds KAP1 and increases ATM-induced phosphorylation of KAP1-Serine 824 (Ser824), thus enhancing DNA damage repair and tumor activation. (2). a MAGEs binding to KAP1 induces p53 degradation and repression of p53 targeted genes. b MAGE-A proteins can directly interact with p53 leading to obstruction of p53 binding to p53-responsive promoters. c MAGE-A proteins also inhibit p53 transcription functions by recruiting HDAC3 to the binding sites of p53 promoter. (3). MAGEs promote prostate cancer progression via increasing AR activity. MAGE-A11 binds NH2-terminal FXXLF motif of AR and increases AR transcriptional activity by modulating AR interdomain interaction. EGFs stabilize AR-MAGE-A11 complex through the site-specific phosphorylation of Thr-360 and subsequent ubiquitinylation of Lys-240, Lys-245 within MAGE homology domain.

Fig. 3

Model of epigenetic regulation of MAGEs in cancer progression. MAGE family can be activated by DNA hypomethylation, histone acetylation, histone methylation, and nucleosome depletion, eventually contributing to oncogenesis. At the same time, MAGEs might be regulated by ceRNA network through miRNAs as the mediators.