The up-regulation of histone deacetylase 8 promotes proliferation and inhibits apoptosis in hepatocellular carcinoma.
BACKGROUND
Histone 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.


OBJECTIVE
The 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.


METHODS
First, 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.


RESULTS
Our 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.


CONCLUSIONS
Our 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.
Jian
J
Wu
Chengli
C
Du
Zhen
Z
Lv
Chaofeng
C
Ding
Jun
J
Cheng
Haiyang
H
Xie
Lin
L
Zhou
Shusen
S
Zheng
D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D005260:Female; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases