Research Papers:

MAGE-A11 is activated through TFCP2/ZEB1 binding sites de-methylation as well as histone modification and facilitates ESCC tumor growth

Shina Liu, Fei Liu, Weina Huang, Lina Gu, Lingjiao Meng, Yingchao Ju, Yunyan Wu, Juan Li, Lihua Liu and Meixiang Sang _

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Oncotarget. 2018; 9:3365-3378. https://doi.org/10.18632/oncotarget.22973

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Shina Liu1,*, Fei Liu1,*, Weina Huang1, Lina Gu1, Lingjiao Meng1, Yingchao Ju1,2, Yunyan Wu1, Juan Li1, Lihua Liu1 and Meixiang Sang1,3

1Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, P. R. China

2Animal Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, P. R. China

3Tumor Research Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, P. R. China

*These authors contributed equally to this work

Correspondence to:

Meixiang Sang, email: [email protected]

Keywords: MAGE-A11; ESCC; DNA methylation; histone acetylation; histone methylation

Received: September 30, 2017     Accepted: November 15, 2017     Published: December 05, 2017


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.

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