The Up-Regulation of Histone Deacetylase 8 Promotes Proliferation and Inhibits Apoptosis in Hepatocellular Carcinoma
The Up-Regulation of Histone Deacetylase 8 Promotes Proliferation and Inhibits Apoptosis in Hepatocellular Carcinoma
复制标题
组蛋白脱乙酰酶 8 的上调促进肝细胞癌增殖并抑制细胞凋亡
DOI：
10.1007/s10620-013-2867-7
复制
发表时间：
2013-12-01
影响因子：
3.1
通讯作者：
Zheng, Shusen
中科院分区：
文献类型：
--
作者：
Wu, Jian;Du, Chengli;Zheng, Shusen
背景组蛋白去乙酰化酶8（HDAC 8）是I类HDAC的成员之一，参与转录调控、细胞周期进程和发育过程，并在肿瘤发生中发挥重要作用。目的探讨HDAC 8在肝癌组织中的表达及HDAC 8基因敲减对肝癌细胞增殖和凋亡的影响，并探讨其可能的作用机制。免疫组织化学染色和蛋白质印迹检测HDAC 8在肝癌细胞系和组织中的mRNA和蛋白表达。然后，我们评估了临床病理参数和HDAC 8蛋白表达之间的相关性。此外，我们采用干扰RNA的方法，探讨HDAC 8在肝癌的进展在vitro.ResultsOur结果表明，HDAC 8的表达显着上调，无论是在肝癌细胞系和肿瘤组织相比，人正常肝细胞系LO 2和相应的非肿瘤组织。此外，我们发现HDAC 8基因敲低可以显着抑制肝癌细胞的增殖，并在体外增加凋亡率。Western blot结果显示，HDAC 8基因敲低后，内源性凋亡途径蛋白（包括BAX、BAD和巴克）升高。内源性凋亡途径下游的caspase-3和PARP的裂解也增强。此外，HDAC 8的抑制也提高了p53的表达和乙酰化的p53在Lys 382，而乙酰化的p53在Lys 373并没有改变.ConclusionsOur的研究表明，HDAC 8在HCC中过表达。HDAC 8基因敲低通过上调p53表达和p53在Lys 382的乙酰化抑制HCC中的肿瘤生长并增强细胞凋亡。HDAC 8可能成为HCC治疗的潜在靶点。
BackgroundHistone deacetylase 8 (HDAC8), a member of class I HDACs, has been reported to be involved in transcriptional regulation, cell cycle progression, and developmental events, and several studies have shown that HDAC8 plays a critical role in tumorigenesis. However, the expression level and the potential role of HDAC8 in hepatocellular carcinoma (HCC) remain unclear.AimThe purpose of this study was to investigate protein expression of HDAC8 in HCC tissues and the effects of HDAC8 knockdown on the proliferation and apoptosis of liver cancer cells, and to explore the possible mechanisms.MethodsFirst, we used quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemical staining, and western blot to examine the mRNA and protein expression of HDAC8 in HCC cell lines and tissues. Then, we assessed the correlation between clinicopathological parameters and the protein expression of HDAC8. Furthermore, we employed the interfering RNA method to explore the potential role of HDAC8 in HCC progression in vitro.ResultsOur results showed that expression of HDAC8 was significantly up-regulated both in HCC cell lines and tumor tissues compared to human normal liver cell line LO2 and corresponding non-tumor tissues. Moreover, we found that HDAC8 knockdown could dramatically inhibit HCC cell proliferation and enhance the apoptosis rate in vitro. Western blot revealed that intrinsic apoptotic pathway proteins, including BAX, BAD, and BAK, were elevated after HDAC8 knockdown. The cleavage of caspase-3 and PARP, which are downstream of intrinsic apoptotic pathway, were also enhanced. In addition, suppression of HDAC8 also elevated the expression of p53 and acetylation of p53 at Lys382, whereas the acetylation of p53 at Lys373 did not change.ConclusionsOur study revealed that HDAC8 was overexpressed in HCC. HDAC8 knockdown suppresses tumor growth and enhances apoptosis in HCC via elevating the expression of p53 and acetylation of p53 at Lys382. HDAC8 might serve as a potential therapeutic target in HCC.