DNA methylation and nucleosome occupancy regulate the cancer germline antigen gene MAGEA11

Smitha R. James, Carlos D. Cedeno, Ashok Sharma, Wa Zhang, James L. Mohler, Kunle Odunsi, Elizabeth M. Wilson, Adam R Karpf

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

MAGEA11 is a cancer germline (CG) antigen and androgen receptor co-activator. Its expression in cancers other than prostate, and its mechanism of activation, has not been reported. In silico analyses reveal that MAGEA11 is frequently expressed in human cancers, is increased during tumor progression, and correlates with poor prognosis and survival. In prostate and epithelial ovarian cancers (EOC), MAGEA11 expression was associated with promoter and global DNA hypomethylation, and with activation of other CG genes. Pharmacological or genetic inhibition of DNA methyltransferases (DNMTs) and/or histone deacetylases (HDACs) activated MAGEA11 in a cell line specific manner. MAGEA11 promoter activity was directly repressed by DNA methylation, and partially depended on Sp1, as pharmacological or genetic targeting of Sp1 reduced MAGEA11 promoter activity and endogenous gene expression. Importantly, DNA methylation regulated nucleosome occupancy specifically at the -1 positioned nucleosome of MAGEA11. Methylation of a single Ets site near the transcriptional start site (TSS) correlated with -1 nucleosome occupancy and, by itself, strongly repressed MAGEA11 promoter activity. Thus, DNA methylation regulates nucleosome occupancy at MAGEA11, and this appears to function cooperatively with sequence-specific transcription factors to regulate gene expression. MAGEA11 regulation is highly instructive for understanding mechanisms regulating CG antigen genes in human cancer.

Original languageEnglish (US)
Pages (from-to)849-863
Number of pages15
JournalEpigenetics
Volume8
Issue number8
DOIs
Publication statusPublished - 2013

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Keywords

  • Cancer germline genes
  • Cancer testis genes
  • DNA methylation
  • Epigenetics
  • MAGEA11
  • Nucleosome occupancy

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

James, S. R., Cedeno, C. D., Sharma, A., Zhang, W., Mohler, J. L., Odunsi, K., ... Karpf, A. R. (2013). DNA methylation and nucleosome occupancy regulate the cancer germline antigen gene MAGEA11. Epigenetics, 8(8), 849-863. https://doi.org/10.4161/epi.25500