HDAC2 inhibits EMT-mediated cancer metastasis by downregulating the long noncoding RNA H19 in colorectal cancer

被引:93
作者
Hu, Xue-ting [1 ,2 ]
Xing, Wei [1 ]
Zhao, Rong-sen [1 ]
Tan, Yan [1 ]
Wu, Xiao-feng [1 ]
Ao, Luo-quan [1 ]
Li, Zhan [1 ]
Yao, Meng-wei [1 ]
Yuan, Mu [1 ]
Guo, Wei [1 ]
Li, Shang-ze [3 ]
Yu, Jian [4 ]
Ao, Xiang [1 ]
Xu, Xiang [1 ]
机构
[1] Army Med Univ, State Key Lab Trauma Burn & Combined Injury, Daping Hosp, Dept Stem Cell & Regenerat Med, Chongqing 400042, Peoples R China
[2] Army Med Univ, Coll Basic Med Sci, Dept Biochem & Mol Biol, Chongqing 400042, Peoples R China
[3] Wuhan Univ, Zhongnan Hosp, Med Sci Res Ctr, Wuhan 430071, Peoples R China
[4] Univ Pittsburgh, UPMC Hillman Canc Ctr, Dept Pathol, Pittsburgh, PA 15213 USA
基金
中国国家自然科学基金;
关键词
CRC; Metastasis; HDAC2; H19; EMT; EPITHELIAL-MESENCHYMAL TRANSITION; PREDICTS POOR-PROGNOSIS; CELL-MIGRATION; HISTONE DEACETYLASES; EXPRESSION; IDENTIFICATION; PROGRESSION; INDUCTION; INVASION; MUTATION;
D O I
10.1186/s13046-020-01783-9
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background 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. Methods 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. Results 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. Conclusion Our study supports HDAC2 as a CRC metastasis suppressor through the inhibition of EMT and the expression of H19 and MMP14.
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页数:14
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