Epigenetic silencing of the RASSF1A tumor suppressor gene through HOXB3-mediated induction of DNMT3B expression.
Epigenetic silencing of the RASSF1A tumor suppressor gene through HOXB3-mediated induction of DNMT3B expression.
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DOI：
10.1016/j.molcel.2009.10.009
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发表时间：
2009-10-23
期刊：
影响因子：
16
通讯作者：
Green MR
中科院分区：
文献类型：
--
作者：
Palakurthy RK;Wajapeyee N;Santra MK;Gazin C;Lin L;Gobeil S;Green MR
RASSF1A肿瘤抑制基因在多种癌症中表观遗传学沉默。在这里，我们进行了全基因组人类shRNA筛选，发现RASSF1A的表观遗传沉默需要同源框蛋白HOXB 3。我们发现HOXB 3与DNA甲基转移酶DNMT 3B基因结合并增加其表达。DNMT3B又被募集到RASSF1A启动子，导致RASSF1A表达的超甲基化和沉默。通过与Polycomb阻遏物复合物2和MYC的相互作用促进DNMT3B募集，MYC与RASSF1A启动子结合。小鼠异种移植实验表明，HOXB 3的致癌活性至少部分是由于RASSF1A的表观遗传沉默。人肺腺癌样品中的表达分析揭示，RASSF1A沉默与HOXB 3和DNMT 3B的过表达强烈相关。对人类癌细胞系的分析表明，这里描述的RASSF1A表观遗传沉默机制可能在不同的癌症类型中很常见。
The RASSF1A tumor suppressor gene is epigenetically silenced in a variety of cancers. Here we perform a genome-wide human shRNA screen and find that epigenetic silencing of RASSF1A requires the homeobox protein HOXB3. We show that HOXB3 binds to the DNA methyltransferase DNMT3B gene and increases its expression. DNMT3B, in turn, is recruited to the RASSF1A promoter, resulting in hypermethylation and silencing of RASSF1A expression. DNMT3B recruitment is facilitated through interactions with Polycomb repressor complex 2 and MYC, which is bound to the RASSF1A promoter. Mouse xenograft experiments indicate that the oncogenic activity of HOXB3 is due, at least in part, to epigenetic silencing of RASSF1A. Expression analysis in human lung adenocarcinoma samples reveals that RASSF1A silencing strongly correlates with over-expression of HOXB3 and DNMT3B. Analysis of human cancer cell lines indicates that the RASSF1A epigenetic silencing mechanism described here may be common in diverse cancer types.
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