Abstract
Recently, we have reported that the product of Melanoma Antigens Genes (MAGE) family member MAGE-A11 is an independent poor prognostic marker for esophageal squamous cell carcinoma (ESCC). However, the reason how MAGE-A11 is activated in ESCC progression still remains unclear. In the current study, we demonstrated that DNA methylation and the subsequent histone posttranslational modifications play crucial roles in the regulation of MAGE-A11 in ESCC progression. We found that the methylation rate of TFCP2/ZEB1 binding site on MAGE-A11 promoter in ESCC tissues and cells is higher than the normal esophageal epithelial tissues and cells. Transcription factors TFCP2 and ZEB1 directly bind MAGE-A11 promoter and regulate the endogenous MAGE-A11 expression in a methylation-dependent manner in ESCC cells. Following MAGE-A11 promoter methylation, the methyl-CpG-binding protein MeCP2 was found to bind the methylated MAGE-A11 promoter to mediate histone deactylation by recruiting HDAC1 and HDAC2. Simultaneously, histone inactivation marks including H3K27me3 as well as H3K9me3 were increased, whereas histone activation mark H3K4me3 was decreased. HDAC inhibitor Trichostatin A (TSA) increased DNA methylase inhibitor Decitabine (DAC)-induced MAGE-A11 expression. siRNA-mediated knockdown of histone methltransferase EZH2 or DZNep (a EZH2 inhibitor) treatment increased DAC-induced MAGE-A11 expression. Our results indicate that MAGE-A11 is activated through DNA demethylation, histone acetylation and histone methylation in ESCC, and its activation promotes ESCC tumor growth.
Highlights
The Melanoma Antigens Genes (MAGE) proteins are a group of highly conserved family members that contain a common MAGE homology domain (MHD) [1]
Our present study showed that MAGE-A11 is not expressed in the normal esophageal epithelial tissues, but expressed in 56.6% of esophageal squamous cell carcinoma (ESCC) tissues (Figure 1A; Supplementary Table 1)
We found that MAGE-A11 expression was positively associated with tumor invasion, lymph node metastasis, distant metastasis or recurrence, TNM stage, histological grade of ESCC patients (Supplementary Table 2)
Summary
The Melanoma Antigens Genes (MAGE) proteins are a group of highly conserved family members that contain a common MAGE homology domain (MHD) [1]. 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 [2,3,4]. In addition to their significance as cancer immunotherapeutic targets, MAGE gene products may contribute to cancer progression as oncoproteins [5, 6]. MAGE proteins interact with transcription factors and function as co-regulators in cancer progression [12,13,14,15].
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