The functional and mechanistic relatedness of EZH2 and menin in hepatocellular carcinoma.
OBJECTIVE
The alterations of histone modification may serve as a promising diagnostic biomarker of hepatocellular carcinoma (HCC), but the clinical and mechanistic relatedness of the histone H3 lysine 27 and 4 trimethylation (H3K27me3 and H3K4me3) in HCC remains poorly understood. Here we propose that the combination of H3K27me3 and H3K4me3 is a more precise predictive/prognostic value for outcome of HCC patients.


METHODS
We used chromatin immunoprecipitation (ChIP) assays and a ChIP-on-chip screen to analyse HCC.


RESULTS
We found that the EZH2 occupancy coincides with the H3K27me3 at promoters and directly silences the transcription of target genes in HCC. The H3K27me3-related gene network of EZH2 contains well-established genes, such as CDKN2A, as well as previously unappreciated genes, including FOXO3, E2F1, and NOTCH2, among others. We further observed independently increasing profiles of H3K27me3 and H3K4me3 at the promoters of certain target genes in HCC specimens. Importantly, Kaplan-Meier analysis reveals that 3-year overall and tumour-free survival rates are dramatically reduced in patients that simultaneously express EZH2 and menin, compared to rates in the EZH2 or menin under expressing patients. Furthermore, an inhibitor of H3K27me3 alone, or in combination with an H3K4me3 inhibitor, effectively blocked the aggressive phenotype of HCC cells.


CONCLUSIONS
Our results indicate that a combined analysis of both H3K27me3 and H3K4me3 may serve as powerful diagnostic biomarkers of HCC, and targeting both might benefit anti-HCC therapy.
Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China; Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China; State Key Laboratory of Cellular Stress Biology, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China.
Shu-Bin
SB
Gao
Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China; Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China.
Bin
B
Xu
Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China.
Li-Hong
LH
Ding
Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China.
Qi-Lin
QL
Zheng
Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China; Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China.
Li
L
Zhang
Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China; Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China; State Key Laboratory of Cellular Stress Biology, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China.
Qi-Fan
QF
Zheng
Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China; Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China.
Shan-Hua
SH
Li
Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China.
Zi-Jie
ZJ
Feng
Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China; Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China.
Jie
J
Wei
Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China; Department of Hepatobiliary Surgery, Affiliated Zhongshan Hospital of Xiamen University, Hubin South Road 201-209, 361004, PR China.
Zhen-Yu
ZY
Yin
Department of Cancer Biology, University of Pennsylvania, BRBII/III, Room 412, 421 Curie Blvd, Philadelphia, PA 19096, USA.
Xianxin
X
Hua
Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China; Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China; State Key Laboratory of Cellular Stress Biology, Xiamen University, Chengzhi Building 110, Xiang'an South Road, Xiamen 361102, PR China. Electronic address: ghjin@xmu.edu.cn.
Guang-Hui
GH
Jin
D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009367:Neoplasm Staging; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D011379:Prognosis; D011499:Protein Processing, Post-Translational / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*
D006657:Histones; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
Hepatocellular carcinoma; Histone methylation; Polycomb; Trithorax