Advertisement

Digestive Diseases and Sciences

, Volume 64, Issue 2, pp 439–446 | Cite as

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

  • Yiping Li
  • Didi Guo
  • Rui Sun
  • Ping Chen
  • Qi Qian
  • Hong FanEmail author
Original Article
  • 97 Downloads

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.

Keywords

H3K9me2 H3K9me3 H3K27me3 Epigenetic marks Gastric cancer 

Notes

Acknowledgments

This work was supported by the grants from National Natural Science Foundation of China (81672414 and 81472548). This work was also supported by the Innovation Capability Development Project of Jiangsu Province (BM2015004).

Compliance with ethical standards

Conflict of interest

We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

Supplementary material

10620_2018_5341_MOESM1_ESM.tif (11.8 mb)
Fig. S1 The expression patterns for the stained histone markers by IHC assay. The expression was scored according to the staining intensity and staining area. The staining intensity was marked as the following, 0 for no staining, 1 for weak staining, 2 for moderate staining, 3 for intensive staining. Based on the percentage of positive cells in the observed epithelial tissues, the staining area was identified as 5 different levels. 0 for 0–5% positive cells, 1, 2, 3, 4 for 6–25%, 26–50%, 51–75%, and 76–100%, respectively. The final score is the product of the staining intensity and staining area. Low indicates for the tissues with the final score ≤ 8, high for the final score > 8. Scale bar = 200 μm (TIFF 12090 kb)
10620_2018_5341_MOESM2_ESM.docx (19 kb)
Supplementary material 2 (DOCX 18 kb)

References

  1. 1.
    Aoyama T, Yoshikawa T. Adjuvant therapy for locally advanced gastric cancer. Surg Today. 2017;47:1295–1302.CrossRefGoogle Scholar
  2. 2.
    Correa P. Gastric cancer: overview. Gastroenterol Clin N Am. 2013;42:211–217.CrossRefGoogle Scholar
  3. 3.
    Li T, Mo X, Fu L, Xiao B, Guo J. Molecular mechanisms of long noncoding RNAs on gastric cancer. Oncotarget. 2016;7:8601–8612.Google Scholar
  4. 4.
    Cheetham SW, Gruhl F, Mattick JS, Dinger ME. Long noncoding RNAs and the genetics of cancer. Br J Cancer. 2013;108:2419–2425.CrossRefGoogle Scholar
  5. 5.
    Hirst M, Marra MA. Epigenetics and human disease. Int J Biochem Cell Biol. 2009;41:136–146.CrossRefGoogle Scholar
  6. 6.
    Panani AD. Cytogenetic and molecular aspects of gastric cancer: clinical implications. Cancer Lett. 2008;266:99–115.CrossRefGoogle Scholar
  7. 7.
    Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074–1080.CrossRefGoogle Scholar
  8. 8.
    Jeltsch A, Jurkowska RZ. New concepts in DNA methylation. Trends Biochem Sci. 2014;39:310–318.CrossRefGoogle Scholar
  9. 9.
    Yang WY, Gu JL, Zhen TM. Recent advances of histone modification in gastric cancer. J Cancer Res Therapeut. 2014;10 Suppl:240–245.Google Scholar
  10. 10.
    Mulero-Navarro S, Esteller M. Epigenetic biomarkers for human cancer: the time is now. Crit Rev Oncol/Hematol. 2008;68:1–11.CrossRefGoogle Scholar
  11. 11.
    Noma K, Allis CD, Grewal SI. Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science. 2001;293:1150–1155.CrossRefGoogle Scholar
  12. 12.
    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.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefGoogle Scholar
  15. 15.
    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.Google Scholar
  16. 16.
    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.CrossRefGoogle Scholar
  17. 17.
    Cao R, Wang L, Wang H, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–1043.CrossRefGoogle Scholar
  18. 18.
    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.CrossRefGoogle Scholar
  19. 19.
    Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006;6:846–856.CrossRefGoogle Scholar
  20. 20.
    Plath K, Fang J, Mlynarczyk-Evans SK, et al. Role of histone H3 lysine 27 methylation in X inactivation. Science. 2003;300:131–135.CrossRefGoogle Scholar
  21. 21.
    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.CrossRefGoogle Scholar
  22. 22.
    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.CrossRefGoogle Scholar
  23. 23.
    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.CrossRefGoogle Scholar
  24. 24.
    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.CrossRefGoogle Scholar
  25. 25.
    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.CrossRefGoogle Scholar
  26. 26.
    Zhang T, Cooper S, Brockdorff N. The interplay of histone modifications—writers that read. EMBO Rep. 2015;16:1467–1481.CrossRefGoogle Scholar
  27. 27.
    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.CrossRefGoogle Scholar
  28. 28.
    Alam H, Gu B, Lee MG. Histone methylation modifiers in cellular signaling pathways. Cell Mol Life Sci CMLS. 2015;72:4577–4592.CrossRefGoogle Scholar
  29. 29.
    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.CrossRefGoogle Scholar
  30. 30.
    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.CrossRefGoogle Scholar
  31. 31.
    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.CrossRefGoogle Scholar
  32. 32.
    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.CrossRefGoogle Scholar
  33. 33.
    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.CrossRefGoogle Scholar
  34. 34.
    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.CrossRefGoogle Scholar
  35. 35.
    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.CrossRefGoogle Scholar
  36. 36.
    Li Q, Wang X, Lu Z, et al. Polycomb CBX7 directly controls trimethylation of histone H3 at lysine 9 at the p16 locus. PLoS ONE. 2010;5:e13732.CrossRefGoogle Scholar
  37. 37.
    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.CrossRefGoogle Scholar
  38. 38.
    Cao Q, Yu J, Dhanasekaran SM, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene. 2008;27:7274–7284.CrossRefGoogle Scholar
  39. 39.
    Chase A, Cross NC. Aberrations of EZH2 in cancer. Cancer Res. 2011;17:2613–2618.Google Scholar
  40. 40.
    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.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medical Genetics and Developmental Biology, Medical School, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of EducationSoutheast UniversityNanjingChina
  2. 2.Department of Pathology, Medical SchoolSoutheast UniversityNanjingChina
  3. 3.Institute of Life Science, The Key Laboratory of Developmental Genes and Human DiseasesSoutheast UniversityNanjingChina
  4. 4.Department of OncologyYancheng First People’s HospitalYanchengChina

Personalised recommendations