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Published in: Digestive Diseases and Sciences 2/2019

01-02-2019 | Original Article

Methylation Patterns of Lys9 and Lys27 on Histone H3 Correlate with Patient Outcome in Gastric Cancer

Authors: Yiping Li, Didi Guo, Rui Sun, Ping Chen, Qi Qian, Hong Fan

Published in: Digestive Diseases and Sciences | Issue 2/2019

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Abstract

Background

Histone methylation has been considered as one of the epigenetic mechanisms of carcinogenesis and progression. Researches on the correlation between histone lysine methylation and gastric cancer (GC) will help in finding novel epigenetic biomarkers for monitoring cancers.

Aims

The study detected the expression patterns of histone 3 lysine 9 dimethylation (H3K9me2), histone 3 lysine 9 trimethylation (H3K9me3), and histone 3 lysine 27 trimethylation (H3K27me3) in GC tissues and evaluated their clinical merit for GC patients.

Methods

One hundred thirty-three paraffin-embedded GC samples were examined by immunohistochemistry for the histone markers: H3K9me2, H3K9me3, and H3K27me3. The relationship and clinicopathological significance of the three lysine methylations on histone H3 with GC were assessed by Paired t test, Chi-square test, Kaplan–Meier analysis with log-rank test, and Cox proportional hazard analyses.

Results

Strong positive immunostaining of H3K9me2, H3K9me3, and H3K27me3 was observed in cancerous tissues than in their counterpart non-cancer tissues. Higher expression patterns of H3K9me2, H3K9me3, and H3K27me3 significantly related to differentiation degree, lymph nodes metastases, and pathological TNM staging in GC. The GC patients with low scoring of the three markers implied long survival period and best prognosis. In contrast, the patients’ survival time was significantly shorter if their cancerous tissues presented high expression of the three markers.

Conclusions

H3K9me2, H3K9me3, and H3K27me3 expression patterns closely relate to clinicopathological features and may be the independent risk factors for the survival of GC patients. The combined pattern of the three markers rather than an individual marker is considered to more accurately evaluate the outcome of GC patients.
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Literature
1.
go back to reference Aoyama T, Yoshikawa T. Adjuvant therapy for locally advanced gastric cancer. Surg Today. 2017;47:1295–1302.CrossRefPubMed Aoyama T, Yoshikawa T. Adjuvant therapy for locally advanced gastric cancer. Surg Today. 2017;47:1295–1302.CrossRefPubMed
2.
go back to reference Correa P. Gastric cancer: overview. Gastroenterol Clin N Am. 2013;42:211–217.CrossRef Correa P. Gastric cancer: overview. Gastroenterol Clin N Am. 2013;42:211–217.CrossRef
3.
go back to reference Li T, Mo X, Fu L, Xiao B, Guo J. Molecular mechanisms of long noncoding RNAs on gastric cancer. Oncotarget. 2016;7:8601–8612.PubMedPubMedCentral Li T, Mo X, Fu L, Xiao B, Guo J. Molecular mechanisms of long noncoding RNAs on gastric cancer. Oncotarget. 2016;7:8601–8612.PubMedPubMedCentral
5.
6.
go back to reference Panani AD. Cytogenetic and molecular aspects of gastric cancer: clinical implications. Cancer Lett. 2008;266:99–115.CrossRefPubMed Panani AD. Cytogenetic and molecular aspects of gastric cancer: clinical implications. Cancer Lett. 2008;266:99–115.CrossRefPubMed
8.
9.
go back to reference Yang WY, Gu JL, Zhen TM. Recent advances of histone modification in gastric cancer. J Cancer Res Therapeut. 2014;10 Suppl:240–245. Yang WY, Gu JL, Zhen TM. Recent advances of histone modification in gastric cancer. J Cancer Res Therapeut. 2014;10 Suppl:240–245.
10.
go back to reference Mulero-Navarro S, Esteller M. Epigenetic biomarkers for human cancer: the time is now. Crit Rev Oncol/Hematol. 2008;68:1–11.CrossRef Mulero-Navarro S, Esteller M. Epigenetic biomarkers for human cancer: the time is now. Crit Rev Oncol/Hematol. 2008;68:1–11.CrossRef
11.
go back to reference Noma K, Allis CD, Grewal SI. Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science. 2001;293:1150–1155.CrossRefPubMed Noma K, Allis CD, Grewal SI. Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science. 2001;293:1150–1155.CrossRefPubMed
12.
go back to reference Peters AH, O’Carroll D, Scherthan H, et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell. 2001;107:323–337.CrossRefPubMed Peters AH, O’Carroll D, Scherthan H, et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell. 2001;107:323–337.CrossRefPubMed
13.
go back to reference Kondo Y, Shen L, Issa JP. Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol Cell Biol. 2003;23:206–215.CrossRefPubMedPubMedCentral Kondo Y, Shen L, Issa JP. Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol Cell Biol. 2003;23:206–215.CrossRefPubMedPubMedCentral
14.
go back to reference Park YS, Jin MY, Kim YJ, Yook JH, Kim BS, Jang SJ. The global histone modification pattern correlates with cancer recurrence and overall survival in gastric adenocarcinoma. Ann Surg Oncol. 2008;15:1968–1976.CrossRefPubMed Park YS, Jin MY, Kim YJ, Yook JH, Kim BS, Jang SJ. The global histone modification pattern correlates with cancer recurrence and overall survival in gastric adenocarcinoma. Ann Surg Oncol. 2008;15:1968–1976.CrossRefPubMed
15.
go back to reference Meng CF, Zhu XJ, Peng G, Dai DQ. Promoter histone H3 lysine 9 di-methylation is associated with DNA methylation and aberrant expression of p16 in gastric cancer cells. Oncol Rep. 2009;22:1221–1227.PubMed Meng CF, Zhu XJ, Peng G, Dai DQ. Promoter histone H3 lysine 9 di-methylation is associated with DNA methylation and aberrant expression of p16 in gastric cancer cells. Oncol Rep. 2009;22:1221–1227.PubMed
16.
go back to reference Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 2002;16:2893–2905.CrossRefPubMedPubMedCentral Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 2002;16:2893–2905.CrossRefPubMedPubMedCentral
17.
go back to reference Cao R, Wang L, Wang H, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–1043.CrossRefPubMed Cao R, Wang L, Wang H, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–1043.CrossRefPubMed
18.
go back to reference Cao R, Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr opin Genet Dev. 2004;14:155–164.CrossRefPubMed Cao R, Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr opin Genet Dev. 2004;14:155–164.CrossRefPubMed
19.
go back to reference Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006;6:846–856.CrossRefPubMed Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006;6:846–856.CrossRefPubMed
20.
go back to reference Plath K, Fang J, Mlynarczyk-Evans SK, et al. Role of histone H3 lysine 27 methylation in X inactivation. Science. 2003;300:131–135.CrossRefPubMed Plath K, Fang J, Mlynarczyk-Evans SK, et al. Role of histone H3 lysine 27 methylation in X inactivation. Science. 2003;300:131–135.CrossRefPubMed
21.
go back to reference Fujii S, Ochiai A. Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells. Cancer Sci. 2008;99:738–746.CrossRefPubMed Fujii S, Ochiai A. Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells. Cancer Sci. 2008;99:738–746.CrossRefPubMed
22.
go back to reference Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K, Yokozaki H. Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci. 2006;97:484–491.CrossRefPubMed Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K, Yokozaki H. Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci. 2006;97:484–491.CrossRefPubMed
23.
go back to reference Zhang L, Zhong K, Dai Y, Zhou H. Genome-wide analysis of histone H3 lysine 27 trimethylation by ChIP-chip in gastric cancer patients. J Gastroenterol. 2009;44:305–312.CrossRefPubMed Zhang L, Zhong K, Dai Y, Zhou H. Genome-wide analysis of histone H3 lysine 27 trimethylation by ChIP-chip in gastric cancer patients. J Gastroenterol. 2009;44:305–312.CrossRefPubMed
24.
go back to reference Zhang W, Li Y, Yang S, et al. Differential mitochondrial proteome analysis of human lung adenocarcinoma and normal bronchial epithelium cell lines using quantitative mass spectrometry. Thorac Cancer. 2013;4:373–379.CrossRefPubMed Zhang W, Li Y, Yang S, et al. Differential mitochondrial proteome analysis of human lung adenocarcinoma and normal bronchial epithelium cell lines using quantitative mass spectrometry. Thorac Cancer. 2013;4:373–379.CrossRefPubMed
25.
go back to reference Varghese F, Bukhari AB, Malhotra R, De A. IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PloS ONE. 2014;9:e96801.CrossRefPubMedPubMedCentral Varghese F, Bukhari AB, Malhotra R, De A. IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PloS ONE. 2014;9:e96801.CrossRefPubMedPubMedCentral
27.
go back to reference Liu F, Wang L, Perna F, Nimer SD. Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape. Nat Rev Cancer. 2016;16:359–372.CrossRefPubMedPubMedCentral Liu F, Wang L, Perna F, Nimer SD. Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape. Nat Rev Cancer. 2016;16:359–372.CrossRefPubMedPubMedCentral
28.
go back to reference Alam H, Gu B, Lee MG. Histone methylation modifiers in cellular signaling pathways. Cell Mol Life Sci CMLS. 2015;72:4577–4592.CrossRefPubMed Alam H, Gu B, Lee MG. Histone methylation modifiers in cellular signaling pathways. Cell Mol Life Sci CMLS. 2015;72:4577–4592.CrossRefPubMed
29.
go back to reference Benard A, Goossens-Beumer IJ, van Hoesel AQ, et al. Histone trimethylation at H3K4, H3K9 and H4K20 correlates with patient survival and tumor recurrence in early-stage colon cancer. BMC Cancer. 2014;14:531.CrossRefPubMedPubMedCentral Benard A, Goossens-Beumer IJ, van Hoesel AQ, et al. Histone trimethylation at H3K4, H3K9 and H4K20 correlates with patient survival and tumor recurrence in early-stage colon cancer. BMC Cancer. 2014;14:531.CrossRefPubMedPubMedCentral
30.
go back to reference Healey MA, Hu R, Beck AH, et al. Association of H3K9me3 and H3K27me3 repressive histone marks with breast cancer subtypes in the Nurses’ Health Study. Breast Cancer Res Treat. 2014;147:639–651.CrossRefPubMed Healey MA, Hu R, Beck AH, et al. Association of H3K9me3 and H3K27me3 repressive histone marks with breast cancer subtypes in the Nurses’ Health Study. Breast Cancer Res Treat. 2014;147:639–651.CrossRefPubMed
31.
go back to reference Yokoyama Y, Matsumoto A, Hieda M, et al. Loss of histone H4K20 trimethylation predicts poor prognosis in breast cancer and is associated with invasive activity. Breast Cancer Res BCR. 2014;16:R66.CrossRefPubMed Yokoyama Y, Matsumoto A, Hieda M, et al. Loss of histone H4K20 trimethylation predicts poor prognosis in breast cancer and is associated with invasive activity. Breast Cancer Res BCR. 2014;16:R66.CrossRefPubMed
32.
go back to reference Chen YW, Kao SY, Wang HJ, Yang MH. Histone modification patterns correlate with patient outcome in oral squamous cell carcinoma. Cancer. 2013;119:4259–4267.CrossRefPubMed Chen YW, Kao SY, Wang HJ, Yang MH. Histone modification patterns correlate with patient outcome in oral squamous cell carcinoma. Cancer. 2013;119:4259–4267.CrossRefPubMed
33.
go back to reference Keung EZ, Akdemir KC, Al Sannaa GA, et al. Increased H3K9me3 drives dedifferentiated phenotype via KLF6 repression in liposarcoma. J Clin Investig. 2015;125:2965–2978.CrossRefPubMedPubMedCentral Keung EZ, Akdemir KC, Al Sannaa GA, et al. Increased H3K9me3 drives dedifferentiated phenotype via KLF6 repression in liposarcoma. J Clin Investig. 2015;125:2965–2978.CrossRefPubMedPubMedCentral
34.
go back to reference Maia LL, Peterle GT, Dos Santos M, et al. JMJD1A, H3K9me1, H3K9me2 and ADM expression as prognostic markers in oral and oropharyngeal squamous cell carcinoma. PLoS ONE. 2018;13:e0194884.CrossRefPubMedPubMedCentral Maia LL, Peterle GT, Dos Santos M, et al. JMJD1A, H3K9me1, H3K9me2 and ADM expression as prognostic markers in oral and oropharyngeal squamous cell carcinoma. PLoS ONE. 2018;13:e0194884.CrossRefPubMedPubMedCentral
35.
go back to reference Sasidharan Nair V, El Salhat H, Taha RZ, John A, Ali BR, Elkord E. DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer. Clin Epigenet. 2018;10:78.CrossRef Sasidharan Nair V, El Salhat H, Taha RZ, John A, Ali BR, Elkord E. DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer. Clin Epigenet. 2018;10:78.CrossRef
36.
37.
go back to reference Cui, H, Hu, Y, Guo, D, Zhang, A, Gu, Y, Zhang, S, et al. DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer. Oncogene 2018;37:4358–4371.CrossRefPubMedPubMedCentral Cui, H, Hu, Y, Guo, D, Zhang, A, Gu, Y, Zhang, S, et al. DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer. Oncogene 2018;37:4358–4371.CrossRefPubMedPubMedCentral
39.
go back to reference Chase A, Cross NC. Aberrations of EZH2 in cancer. Cancer Res. 2011;17:2613–2618. Chase A, Cross NC. Aberrations of EZH2 in cancer. Cancer Res. 2011;17:2613–2618.
40.
go back to reference Chen MW, Hua KT, Kao HJ, et al. H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res. 2010;70:7830–7840.CrossRefPubMed Chen MW, Hua KT, Kao HJ, et al. H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res. 2010;70:7830–7840.CrossRefPubMed
Metadata
Title
Methylation Patterns of Lys9 and Lys27 on Histone H3 Correlate with Patient Outcome in Gastric Cancer
Authors
Yiping Li
Didi Guo
Rui Sun
Ping Chen
Qi Qian
Hong Fan
Publication date
01-02-2019
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 2/2019
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-018-5341-8

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