title: DNA methylation and nucleosome occupancy regulate the cancer germline antigen gene MAGEA11.
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.
authors.affiliation: Department of Pharmacology and Therapeutics; Roswell Park Cancer Institute; Buffalo, NY USA.
authors.forename: Smitha R
authors.initials: SR
authors.lastname: James
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Cedeno
authors.forename: Ashok
authors.initials: A
authors.lastname: Sharma
authors.forename: Wa
authors.initials: W
authors.lastname: Zhang
authors.forename: James L
authors.initials: JL
authors.lastname: Mohler
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
authors.forename: Adam R
authors.initials: AR
authors.lastname: Karpf
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism; D009707:Nucleosomes / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D056572:Histone Deacetylase Inhibitors; C110882:MAGEA11 protein, human; D009363:Neoplasm Proteins; D009707:Nucleosomes; D016329:Sp1 Transcription Factor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases
keywords: DNA methylation; MAGEA11; cancer germline genes; cancer testis genes; epigenetics; nucleosome occupancy