DNA methylation and nucleosome occupancy regulate the cancer germline antigen gene MAGEA11
DNA methylation and nucleosome occupancy regulate the cancer germline antigen gene MAGEA11
复制标题
DOI：
10.4161/epi.25500
复制
发表时间：
2013-08-01
期刊：
影响因子：
3.7
通讯作者：
Karpf, Adam R.
中科院分区：
文献类型：
--
作者：
James, Smitha R.;Cedeno, Carlos D.;Karpf, Adam R.
MAGEA11是一种癌症生殖系(CG)抗原和雄激素受体共激活剂。它在前列腺癌以外的其他肿瘤中的表达及其激活机制尚未见报道。计算机分析表明，MAGEA11在人类癌症中频繁表达，在肿瘤进展过程中表达增加，并与不良预后和生存相关。在前列腺癌和上皮性卵巢癌中，MAGEA11的表达与启动子和全局DNA低甲基化有关，也与其他CG基因的激活有关。药物或遗传抑制DNA甲基转移酶(DNMT)和/或组蛋白脱乙酰酶(HDAC)以细胞系特异性的方式激活MAGEA11。MAGEA11启动子活性直接被DNA甲基化抑制，并且部分依赖于Sp1，因为Sp1的药物或基因靶向降低了MAGEA11启动子活性和内源基因表达。重要的是，DNA甲基化调节了核小体在MAGEA11-1定位的核小体的占有率。转录起始点(TSS)附近单个Ets位点的甲基化与-1核小体占有率相关，并且本身强烈抑制MAGEA11启动子的活性。因此，DNA甲基化调节MAGEA11的核小体占据，这似乎与序列特异的转录因子协同作用来调节基因的表达。MAGEA11的调控对于理解人类癌症中CG抗原基因的调控机制具有重要意义。
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.