DNA methylation-dependent repression of PDZ-LIM domain-containing protein 2 in colon cancer and its role as a potential therapeutic target.
DNA methylation-dependent repression of PDZ-LIM domain-containing protein 2 in colon cancer and its role as a potential therapeutic target.
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DOI：
10.1158/0008-5472.can-09-3263
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发表时间：
2010-03-01
期刊：
影响因子：
11.2
通讯作者：
Xiao G
中科院分区：
文献类型：
--
作者：
Qu Z;Yan P;Fu J;Jiang J;Grusby MJ;Smithgall TE;Xiao G
NF-κB转录因子的结构性激活在慢性结肠炎和结肠肿瘤的发生中起着关键作用。然而，在结肠发病过程中，受到严格调控的NF-κB通路如何被结构性激活的机制仍然不清楚。在此，我们报道了一种重要的NF-κB激活终止子PDLIM2在不同的人类结直肠癌细胞系中被抑制，这提示了NF-κB结构性激活的一个重要机制。事实上，外源性PDLIM2的表达抑制了这些结直肠癌细胞中的NF-κB的结构性激活。重要的是，PDLIM2的表达足以抑制这些恶性细胞的体外锚定非依赖性生长和体内肿瘤形成。我们进一步证明，PDLIM2的抑制涉及启动子甲基化。相应地，用DNA甲基转移酶抑制剂5-氮杂-2‘-脱氧胞苷(5-aza-2’-deoxcytidine，5-aza-DC)处理大肠肿瘤细胞系后，PDLIM2的表达恢复，并导致生长停滞。因此，这些研究通过确定PDLIM2的新的肿瘤抑制作用，为结肠肿瘤的发生提供了新的机制见解。
Constitutive activation of the NF-κB transcription factor plays a key role in chronic colonic inflammation and colon tumorigenesis. However, the mechanisms by which the tightly regulated NF-κB pathway becomes constitutively activated during colonic pathogenesis remain obscure. Here, we report that PDLIM2, an essential terminator of NF-κB activation, is repressed in various human colorectal cancer cell lines, suggesting one important mechanism for the constitutive activation of NF-κB. Indeed, expression of exogenous PDLIM2 inhibited constitutive NF-κB activation in these colorectal cancer cells. Importantly, the PDLIM2 expression was sufficient to suppress in vitro anchorage-independent growth and in vivo tumor formation of these malignant cells. We have further shown that the PDLIM2 repression involves promoter methylation. Accordingly, treatment of the colorectal tumor cell lines with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) restored PDLIM2 expression and resulted in growth arrest. These studies thus provide new mechanistic insights into colon tumorigenesis by identifying a novel tumor suppressor role for PDLIM2.