Involvement of histone deacetylation in MORC2-mediated down-regulation of carbonic anhydrase IX.
Involvement of histone deacetylation in MORC2-mediated down-regulation of carbonic anhydrase IX.
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组蛋白脱乙酰化参与 MORC2 介导的碳酸酐酶 IX 下调
DOI：
10.1093/nar/gkq006
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发表时间：
2010-05
影响因子：
14.9
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Shao Y;Li Y;Zhang J;Liu D;Liu F;Zhao Y;Shen T;Li F
碳酸酐酶IX（CAIX）在肿瘤细胞的生长和存活中起重要作用。MORC 2是MORC蛋白家族的成员。MORC蛋白含有一个CW型锌指结构域，并被预测具有调节转录的功能，但尚未鉴定出MORC 2靶基因。在这里，我们进行了DNA微阵列杂交，发现CAIX mRNA下调8倍时，MORC 2过表达。这一结果通过北方和western印迹分析得到进一步证实。我们的研究结果还表明，保护区4（PR 4）是重要的抑制功能的MORC 2。此外，MORC 2降低了CAIX启动子处组蛋白H3的乙酰化水平。同时，抑制素A（TSA）对CAIX启动子活性具有增强作用。在所测试的六种HDAC中，组蛋白脱乙酰酶4（HDAC 4）对CAIX阻遏具有显著得多的作用。ChIP和ChIP Re-IP测定显示MORC 2和HDAC 4组装在CAIX启动子的相同区域上。重要的是，我们进一步证实了这两种蛋白质同时存在于PR 4结合复合物中。这些结果可能有助于理解CAIX调控的分子机制。
Carbonic anhydrase IX (CAIX) plays an important role in the growth and survival of tumor cells. MORC2 is a member of the MORC protein family. The MORC proteins contain a CW-type zinc finger domain and are predicted to have the function of regulating transcription, but no MORC2 target genes have been identified. Here we performed a DNA microarray hybridization and found CAIX mRNA to be down-regulated 8-fold when MORC2 was overexpressed. This result was further confirmed by northern and western blot analysis. Our results also showed that the protected region 4 (PR4) was important for the repression function of MORC2. Moreover, MORC2 decreased the acetylation level of histone H3 at the CAIX promoter. Meanwhile, trichostatin A (TSA) had an increasing effect on CAIX promoter activity. Among the six HDACs tested, histone deacetylase 4 (HDAC4) had a much more prominent effect on CAIX repression. ChIP and ChIP Re-IP assays showed that MORC2 and HDAC4 were assembled on the same region of the CAIX promoter. Importantly, we further confirmed that both proteins are simultaneously present in the PR4-binding complex. These results may contribute to understanding the molecular mechanisms of CAIX regulation.
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