Increased expression of androgen receptor coregulator MAGE-11 in prostate cancer by DNA hypomethylation and cyclic AMP.
Increased expression of androgen receptor coregulator MAGE-11 in prostate cancer by DNA hypomethylation and cyclic AMP.
复制标题
通过 DNA 低甲基化和环 AMP 增加前列腺癌中雄激素受体共调节因子 MAGE-11 的表达。
DOI：
10.1158/1541-7786.mcr-08-0400
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发表时间：
2009-04
影响因子：
5.2
通讯作者：
Wilson, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Karpf, Adam R.;Bai, Suxia;James, Smitha R.;Mohler, James L.;Wilson, Elizabeth M.
癌症种系抗原 MAGE 家族的黑色素瘤抗原基因蛋白 A11 (MAGE-11) 通过与 AR NH2 末端 FXXLF 基序相互作用，增加雄激素受体 (AR) 转录活性。本研究调查了雄激素剥夺治疗和前列腺癌进展期间控制 MAGE-11 表达的调节机制。研究包括人类前列腺癌的 CWR22 异种移植模型、良性和恶性前列腺的临床标本以及前列腺癌细胞系。在雄激素剥夺治疗和前列腺癌进展过程中，MAGE-11 mRNA 水平增加了 100 至 1500 倍，其中在去势复发性 CWR22 异种移植物和去势复发性前列腺癌的临床标本中水平最高。对前列腺癌标本和细胞系的基因组 DNA 进行焦磷酸测序表明，MAGE-11 的增加是由于 MAGE-11 基因 5' 启动子中 CpG 岛的 DNA 低甲基化所致。对良性和恶性前列腺肿瘤和前列腺癌细胞系的基因组 DNA 进行亚硫酸氢钠测序表明，转录起始位点各个 CpG 位点的 DNA 低甲基化对于 MAGE-11 的表达最为关键。环 AMP 还增加前列腺癌细胞系中 MAGE-11 的表达和 AR 转录活性。然而，环状 AMP 不会改变启动子的 DNA 甲基化，并且其作用受到 MAGE-11 启动子区域广泛 DNA 甲基化的抑制。通过启动子 DNA 低甲基化和环 AMP 增加 AR 核心调节因子 MAGE-11 的表达，为去势复发性前列腺癌中增加 AR 信号传导提供了新机制。
Melanoma antigen gene protein-A11 (MAGE-11) of the MAGE family of cancer-germline antigens increases androgen receptor (AR) transcriptional activity through its interaction with the AR NH2-terminal FXXLF motif. The present study investigated the regulatory mechanisms that control MAGE-11 expression during androgen deprivation therapy and prostate cancer progression. Studies include the CWR22 xenograft model of human prostate cancer, clinical specimens of benign and malignant prostate, and prostate cancer cell lines. MAGE-11 mRNA levels increased 100 to 1500 fold during androgen deprivation therapy and prostate cancer progression, with highest levels in the castration-recurrent CWR22 xenograft and clinical specimens of castration-recurrent prostate cancer. Pyrosequencing of genomic DNA from prostate cancer specimens and cell lines indicated the increase in MAGE-11 resulted from DNA hypomethylation of a CpG island in the 5´ promoter of the MAGE-11 gene. Sodium bisulfite sequencing of genomic DNA from benign and malignant prostate tumors and prostate cancer cell lines revealed DNA hypomethylation at individual CpG sites at the transcription start site were most critical for MAGE-11 expression. Cyclic AMP also increased MAGE-11 expression and AR transcriptional activity in prostate cancer cell lines. However, cyclic AMP did not alter DNA methylation of the promoter and its effects were inhibited by extensive DNA methylation in the MAGE-11 promoter region. Increased expression of the AR coregulator MAGE-11 through promoter DNA hypomethylation and cyclic AMP provides a novel mechanism for increased AR signaling in castration-recurrent prostate cancer.