Switch to full-length of XAF1 mRNA expression in prostate cancer cells by the DNA methylation inhibitor
Switch to full-length of XAF1 mRNA expression in prostate cancer cells by the DNA methylation inhibitor
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DOI：
10.1002/ijc.21636
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发表时间：
2006-05-15
影响因子：
6.4
通讯作者：
Xu, DW
中科院分区：
文献类型：
--
作者：
Fang, XL;Liu, ZX;Xu, DW
X-linked inhibitor of apoptosis protein （XIAP）通过与caspases结合并抑制其功能抑制凋亡细胞死亡，而XIAP-associated factor1 (XAF1)，一种锌指蛋白，拮抗XIAP活性，从而促进细胞凋亡。最近在各种类型的癌细胞中发现了XAF1基因的异常沉默，这被认为是恶性细胞生存优势的潜在机制之一。在本研究中，我们研究了XAF1在前列腺癌细胞中的表达。与以全长XAF1 mRNA为主的正常组织相比，LNCaP和DU145前列腺癌细胞株仅表达短形式的XAF1转录本，而PC3细胞则表现出XAF1基因的完全沉默。DNA甲基化抑制导致LNCaP和DU145细胞中XAF1 mRNA表达的全长转换。在6/8的前列腺癌患者肿瘤样品中也观察到XAF1表达下调。我们的研究结果表明，剪接改变或下调XAF1转录本可能发生在前列腺癌的发展过程中，由于异常的DNA甲基化。XAF1 mRNA的选择性剪接导致XAF1蛋白的锌指结构域缺失19个氨基酸，这可能会影响其与XIAP的功能相互作用，因此，通过破坏凋亡机制的平衡，有助于前列腺癌的发病。(c) 2005 Wiley-Liss, Inc。
X-linked inhibitor of apoptosis protein (XIAP) suppresses apoptotic cell death by binding to caspases and inhibiting their functions, while the XIAP-associated factor1 (XAF1), a zinc finger protein, antagonizes XIAP activities, thereby promoting apoptosis. The aberrant silence of the XAF1 gene has recently been found in various types of cancer cells, which is suggested to be one of the potential mechanisms underlying survival advantages of malignant cells. In the present study, we investigated the XAF1 expression in prostate cancer cells. Compared with normal tissues where a full-length of XAF1 mRNA is predominant, LNCaP and DU145 prostate cancer cell lines only expressed a short form of XAF1 transcripts, whereas PC3 cells exhibited a complete silence of the XAF1 gene. Inhibition of DNA methylation led to a switch to the full length of XAF1 mRNA expression in LNCaP and DU145 cells. The down-regulation of XAF1 expression was also observed in 6/8 tumor samples derived front patients with prostate cancer. Our findings suggest that splicing alterations or downregulation of the XAF1 transcript may occur during the development of prostate cancers due to the aberrant DNA methylation. The alternative splicing of XAF1 mRNA leads to formation of a truncated XAF1 protein with 19 amino acid deletion in its zinc finger domain, which likely affects its functional interaction with XIAP, and consequently, contributes to the pathogenesis of prostate cancers by disrupting balance of the apoptosis machinery. (c) 2005 Wiley-Liss, Inc.