Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4a-cyclin D1-CDK 4/6-pRb-E2F1 pathway
Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4a-cyclin D1-CDK 4/6-pRb-E2F1 pathway
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DOI：
10.1158/0008-5472.can-07-0529
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发表时间：
2007-06-15
期刊：
影响因子：
11.2
通讯作者：
Jang, Kyung Lib
中科院分区：
文献类型：
--
作者：
Jung, Jin Kyu;Arora, Payal;Jang, Kyung Lib
DNA甲基转移酶1（DNMT1）在DNA复制过程中负责将DNA甲基化模式复制到子链上。其在人类肿瘤（包括肝细胞癌）中经常表达上调，但过表达的机制及其生物学意义仍不清楚。在此，我们发现乙肝病毒X蛋白（HBx）通过一个涉及p16(INK4a)-细胞周期蛋白D1 - 细胞周期蛋白依赖性激酶（CDK）4/6 - 视网膜母细胞瘤蛋白（pRb）- E2F1通路的调节回路激活DNMT1的表达。HBx诱导p16(INK4)启动子的DNA高甲基化以抑制其表达，这随后导致G1 - CDK的激活、pRb的磷酸化、E2F1的激活，并最终导致DNMT1的转录激活。通过用5'-氮杂-2'-脱氧胞苷处理或引入DNMT1小干扰RNA抑制DNMT1活性，不仅消除了DNA甲基化介导的p16(INK4a)抑制，而且损害了DNMT1自身的表达，这表明DNMT1和p16(INK4a)之间存在相互作用。HBx对细胞周期蛋白D1的上调可能作为该回路的起始冲动，因为它对DNMT1表达的激活是绝对必需的。我们还观察到通过该途径积累的DNMT1通过启动子高甲基化使E - 钙黏蛋白表达失活。考虑到pRb - E2F1通路在人类肿瘤中普遍被激活，该回路的激活可能很广泛，并且是一个潜在的治疗靶点。
DNA methyltransferase 1 (DNMT1) is responsible for copying DNA methylation patterns to the daughter strands during DNA replication. Its expression is frequently up-regulated in human tumors, including hepatocellular carcinoma, but the mechanism of overexpression and its biological significance remain unclear. Here, we show that hepatitis B virus X protein (HBx) activates DNMT1 expression via a regulatory circuit involving the p16(INK4a)-cyclin D1-cyclin-dependent kinase (CDK) 4/6-retinoblastoma protein (pRb)-E2F1 pathway. HBx induced DNA hypermethylation of p16(INK4), promoter to repress its expression, which subsequently led to activation of GI-CDKs, phosphorylation of pRb, activation of E2F1, and finally transcriptional activation of DNMT1. Inhibition of DNMT1 activity by either treatment with 5'-Aza-2'dC or introduction of DNMT1 small interfering RNA not only abolished the DNA methylation-mediated p16(INK4a) repression but also impaired DNMT1 expression itself, suggesting a cross-talk between DNMT1 and p16(INK4a). The up-regulation of cyclin D1 by HBx is likely to serve as an initiative impulse for the circuit because it was absolutely required for the activation of DNMT1 expression. We also observed that accumulated DNMT1 via this pathway inactivates E-cadherin expression through promoter hypermethylation. Considering that the pRb-E2F1 pathway is commonly activated in human tumors, activation of this circuit might he widespread and a potential therapeutic target.