HDAC2 inhibits EMT-mediated cancer metastasis by downregulating the long noncoding RNA H19 in colorectal cancer.
HDAC2 inhibits EMT-mediated cancer metastasis by downregulating the long noncoding RNA H19 in colorectal cancer.
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HDAC2通过下调结直肠癌中的长非编码RNA H19抑制EMT介导的癌症转移
DOI：
10.1186/s13046-020-01783-9
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发表时间：
2020-12-02
期刊：
影响因子：
--
通讯作者：
Xu X
中科院分区：
文献类型：
--
作者：
Hu XT;Xing W;Zhao RS;Tan Y;Wu XF;Ao LQ;Li Z;Yao MW;Yuan M;Guo W;Li SZ;Yu J;Ao X;Xu X
新出现的证据表明上皮 - 间质转化（EMT）和表观遗传机制促进转移。组蛋白去乙酰化酶（HDACs）和非编码RNA（ncRNAs）是重要的表观遗传调节因子。在此，我们阐明了组蛋白去乙酰化酶2（HDAC2）通过非编码RNA调节EMT和结直肠癌（CRC）转移的一种新作用。
利用公共数据库以及匹配的原发和转移组织，以及具有不同转移潜能的CRC细胞（DLD1、HCT116、SW480和SW620）分析了HDACs在CRC中的表达。利用微阵列分析来鉴定亲本CRC细胞和HDAC2敲除CRC细胞中的差异基因。采用蛋白质印迹法和免疫荧光法测定EMT和组蛋白修饰。通过Transwell实验评估迁移能力，并通过尾静脉注射在体内评估转移情况。通过逆转录 - 聚合酶链反应、染色质免疫沉淀和报告基因实验评估基因表达和调控。通过免疫沉淀评估蛋白质相互作用。使用靶向H19、SP1和MMP14的特异性小干扰RNA来验证它们在HDAC2缺失诱导的EMT和转移中的作用。
HDAC2表达降低与CRC患者预后不良相关，且在CRC转移中发现。HDAC2缺失或敲低通过上调长链非编码RNA H19（LncRNA H19）诱导EMT和转移。HDAC2通过与SP1结合，使启动子中的组蛋白H3K27去乙酰化，从而抑制LncRNA H19的表达。LncRNA H19作为miR - 22 - 3P海绵发挥作用，增加MMP14的表达。HDAC2缺失强烈促进CRC肺转移，而LncRNA H19敲低可抑制这种转移。
我们的研究支持HDAC2通过抑制EMT以及H19和MMP14的表达作为CRC转移的抑制因子。
在线版本包含补充材料，可在10.1186/s13046 - 020 - 01783 - 9获取。
Emerging evidence suggests that epithelial mesenchymal transition (EMT) and epigenetic mechanisms promote metastasis. Histone deacetylases (HDACs) and noncoding RNAs (ncRNAs) are important epigenetic regulators. Here, we elucidated a novel role of histone deacetylase 2 (HDAC2) in regulating EMT and CRC metastasis via ncRNA. The expression of HDACs in CRC was analyzed using the public databases and matched primary and metastatic tissues, and CRC cells with different metastatic potentials (DLD1, HCT116, SW480 and SW620). Microarray analysis was used to identify differential genes in parental and HDAC2 knockout CRC cells. EMT and histone modifications were determined using western blot and immunofluorescence. Migration ability was assessed by transwell assay, and metastasis was assessed in vivo using a tail vain injection. Gene expression and regulation was assessed by RT-PCR, chromatin immunoprecipitation and reporter assays. Protein interaction was assessed by immunoprecipitation. Specific siRNAs targeting H19, SP1 and MMP14 were used to validate their role in HDAC2 loss induced EMT and metastasis. Reduced HDAC2 expression was associated with poor prognosis in CRC patients and found in CRC metastasis. HDAC2 deletion or knockdown induced EMT and metastasis by upregulating the long noncoding RNA H19 (LncRNA H19). HDAC2 inhibited LncRNA H19 expression by histone H3K27 deacetylation in its promoter via binding with SP1. LncRNA H19 functioned as a miR-22-3P sponge to increase the expression of MMP14. HDAC2 loss strongly promoted CRC lung metastasis, which was suppressed LncRNA H19 knockdown. Our study supports HDAC2 as a CRC metastasis suppressor through the inhibition of EMT and the expression of H19 and MMP14. The online version contains supplementary material available at 10.1186/s13046-020-01783-9.
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