Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Functional RNomics Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Cancer Evolution Research Center, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
J Hepatol. 2015 Aug;63(2):408-19. doi: 10.1016/j.jhep.2015.03.019. Epub 2015 Mar 25.
BACKGROUND & AIMS: Most common reason behind changes in histone deacetylase (HDAC) function is its overexpression in cancer. However, among HDACs in liver cancer, HDAC6 is uniquely endowed with a tumor suppressor, but the mechanism underlying HDAC6 inactivation has yet to be uncovered.
Microarray profiling and target prediction programs were used to identify miRNAs targeting HDAC6. A series of inhibitors, activators and siRNAs was introduced to validate regulatory mechanisms for microRNA-221-3p (miR-221) governing HDAC6 in hepatocarcinogenesis.
Comprehensive miRNA profiling analysis identified seven putative endogenous miRNAs that are significantly upregulated in hepatocellular carcinoma (HCC). While miR-221 was identified as a suppressor of HDAC6 by ectopic expression of miRNA mimics in Dicer knockdown cells, targeted-disruption of miR-221 repressed cancer cell growth through derepressing HDAC6 expression. Suppression of HDAC6 via miR-221 was induced by JNK/c-Jun signaling in liver cancer cells but not in normal hepatic cells. Additionally, cytokine-induced NF-κBp65 independently regulated miR-221, thereby suppressing HDAC6 expression in HCC cells. HCC tissues derived from chemical-induced rat and H-ras12V transgenic mice liver cancer models validated that JNK/c-Jun activation and NF-κBp65 nuclear translocation are essential for the transcription of miR-221 leading to repression of HDAC6 in HCC.
Our findings suggest that the functional loss or suppression of the tumor suppressor HDAC6 is caused by induction of miR-221 through coordinated JNK/c-Jun- and NF-κB-signaling pathways during liver tumorigenesis, providing a novel target for the molecular treatment of liver malignancies.
组蛋白去乙酰化酶（HDAC）功能改变的最常见原因是其在癌症中的过度表达。然而，在肝癌中的 HDAC 中，HDAC6 具有独特的肿瘤抑制作用，但 HDAC6 失活的机制尚未被揭示。
使用微阵列分析和靶标预测程序来鉴定靶向 HDAC6 的 miRNA。引入一系列抑制剂、激活剂和 siRNA，以验证 miRNA-221-3p（miR-221）调控肝癌发生过程中 HDAC6 的调控机制。
全面的 miRNA 分析鉴定出七种在肝细胞癌（HCC）中显著上调的内源性 miRNA。通过在 Dicer 敲低细胞中转染 miRNA 模拟物，miR-221 被鉴定为 HDAC6 的抑制物，而靶向破坏 miR-221 通过去抑制 HDAC6 的表达抑制癌细胞生长。在肝癌细胞中，JNK/c-Jun 信号诱导抑制 HDAC6 通过 miR-221，而在正常肝细胞中则不诱导。此外，细胞因子诱导的 NF-κBp65 独立调节 miR-221，从而抑制 HCC 细胞中 HDAC6 的表达。化学诱导的大鼠和 H-ras12V 转基因小鼠肝癌模型的 HCC 组织验证了 JNK/c-Jun 激活和 NF-κBp65 核易位对于 miR-221 的转录以及 HCC 中 HDAC6 的抑制是必需的。
我们的研究结果表明，在肝肿瘤发生过程中，通过协调的 JNK/c-Jun-和 NF-κB 信号通路诱导 miR-221，导致肿瘤抑制因子 HDAC6 的功能丧失或抑制，为肝恶性肿瘤的分子治疗提供了新的靶点。
