Histone deacetylase inhibitor SAHA epigenetically regulates miR-17-92 cluster and MCM7 to upregulate MICA expression in hepatoma.
Histone deacetylase inhibitor SAHA epigenetically regulates miR-17-92 cluster and MCM7 to upregulate MICA expression in hepatoma.
复制标题
组蛋白脱乙酰酶抑制剂 SAHA 通过表观遗传调节 miR-17-92 簇和 MCM7，从而上调肝癌中 MICA 的表达。
DOI：
10.1038/bjc.2014.547
复制
发表时间：
2015-01-06
影响因子：
8.8
通讯作者：
Zhang, C
中科院分区：
文献类型：
--
作者：
Yang, H;Lan, P;Hou, Z;Guan, Y;Zhang, J;Xu, W;Tian, Z;Zhang, C
使用组蛋白去乙酰化酶抑制剂（HDACi）的表观遗传疗法已在治疗人类恶性肿瘤的临床试验中显示出前景。除了对肿瘤细胞生长的直接影响外，HDACi还上调MHC I类相关链分子A和B（云母和MIC B）的表达，导致肿瘤细胞对自然杀伤细胞介导的裂解的敏感性增强。其分子机制尚不清楚。采用启动子乙酰化分析、生物信息学分析和染色质免疫沉淀分析，研究辛二酰苯胺异羟肟酸（SAHA）介导的云母及其相关miRNA表达的转录调控机制。SAHA通过促进MICA相关的组蛋白乙酰化同时抑制云母/B靶向miRNA miR-20 a、miR-93和miR-106 B上调MICA/B的转录。SAHA抑制miRNA转录的机制涉及抑制其宿主基因（miR-17-92簇和MCM 7）。SAHA通过消除STAT 3的酪氨酸磷酸化下调miR-17-92簇，并通过局部组蛋白脱乙酰化降低MCM 7转录。HDACi SAHA通过调节肝癌中miR-17-92簇和MCM 7的表达，表观遗传地上调云母表达，从而增强HCC对自然杀伤细胞介导的裂解的敏感性。这种新的作用机制为HDACi治疗HCC提供了希望。
Epigenetic therapy using histone deacetylase inhibitors (HDACi) has shown promise in clinical trials for the treatment of human malignancies. In addition to the immediate effects on the tumour cell growth, HDACi upregulates the expression of MHC class I-related chain molecules A and B (MICA and MICB), resulting in an enhanced susceptibility of tumour cells to natural killer cell-mediated lysis. The molecular mechanism underlying is still unclear. The transcriptional regulation mechanism underlying suberoylanilide hydroxamic acid (SAHA)-mediated regulation of MICA and related miRNA expression was investigated using promoter acetylation assays, bioinformatics analysis and chromatin immunoprecipitation assay. SAHA upregulates the transcription of MICA/B by promoting MICA-associated histone acetylation while suppressing the MICA/B-targeting miRNAs miR-20a, miR-93 and miR-106b. The mechanism by which SAHA repressed miRNAs transcription involved repression of their host genes (miR-17-92 cluster and MCM7). SAHA downregulated the miR-17-92 cluster by abolishing tyrosine phosphorylation of STAT3 and decreased MCM7 transcription through localised histone deacetylation. The HDACi SAHA epigenetically upregulates MICA expression through regulating the expression of miR-17-92 cluster and MCM7 in hepatoma, thus enhancing the sensitivity of HCC to natural killer cell-mediated lysis. This novel mechanism of action provides promise for HDACi in therapy of HCC.