Molecular Medicine

, Volume 17, Issue 11–12, pp 1137–1145 | Cite as

H3K27me3 Protein Is a Promising Predictive Biomarker of Patients’ Survival and Chemoradioresistance in Human Nasopharyngeal Carcinoma

  • Mu-Yan Cai
  • Zhu-Ting Tong
  • Wei Zhu
  • Zhu-Zhi Wen
  • Hui-Lan Rao
  • Ling-Ling Kong
  • Xin-Yuan Guan
  • Hsiang-Fu Kung
  • Yi-Xin Zeng
  • Dan Xie
Research Article


Trimethylation of lysine 27 on histone H3 (H3K27me3) is an epigenetic change which plays a critical role in tumor development and/or progression. However, the molecular status of H3K27me3 and its clinicopathologic/prognostic significance in nasopharyngeal carcinoma (NPC) have not been elucidated. In this study, the methods of Western blotting and immunohistochemistry (IHC) were utilized to examine the expression of H3K27me3 protein in NPC tissues and nonneoplastic nasopharyngeal epithelial tissues. Receiver operating characteristic (ROC) curve analysis was used to determine the cutpoint for H3K27me3 high expression. High expression of H3K27me3 could be observed in 127/209 (60.8%) of NPCs and in 8/50 (16.0%) normal nasopharyngeal epithelial tissues (P < 0.001). Further correlation analysis demonstrated that high expression of H3K27me3 was positively associated with tumor later T classification, tumor metastasis, advanced clinical stage and chemoradioresistance (P < 0.05). Moreover, high expression of H3K27me3 was closely associated with NPC patient shortened survival time as evidenced by univariate and multivariate analysis (P < 0.05). Consequently, a new clinicopathologic prognostic model with three poor prognostic factors (H3K27me3 expression, distant metastasis and treatment regimen) was constructed. The model could stratify risk significantly (low, intermediate and high) for overall survival and progression-free survival (P < 0.0001). These findings provide evidence that H3K27me3 expression, as examined by IHC, has the potential to be used as an immunomarker to predict NPC chemoradiotherapy response and patient prognosis. The combined clinicopathologic prognostic model may become a useful tool for identifying NPC patients with different clinical outcomes.



This work was supported by the 973 Project of China (2010CB912802 and 2010CB529401) and the Foundation of Guangzhou Science and Technology Bureau, China (2005Z1-E0131).


  1. 1.
    Wei WI, Sham JS. (2005) Nasopharyngeal carcinoma. Lancet. 365:2041–54.CrossRefGoogle Scholar
  2. 2.
    Chang ET, Adami HO. (2006) The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol. Biomarkers Prev. 15:1765–77.CrossRefGoogle Scholar
  3. 3.
    Yamashita S, Kondo M, Hashimoto S. (1985) Squamous cell carcinoma of the nasopharynx. An analysis of failure patterns after radiation therapy. Acta Radiol. Oncol. 24:315–20.CrossRefGoogle Scholar
  4. 4.
    Chua DT, et al. (2005) Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials. J. Clin. Oncol. 23:1118–24.CrossRefGoogle Scholar
  5. 5.
    Chan AT, et al. (1995) A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 33:569–77.CrossRefGoogle Scholar
  6. 6.
    Lin JC, Chen KY, Jan JS, Hsu CY. (1996) Partially hyperfractionated accelerated radiotherapy and concurrent chemotherapy for advanced nasopharyngeal carcinoma Int. J. Radiat. Oncol. Biol. Phys. 36:1127–36.CrossRefGoogle Scholar
  7. 7.
    Al-Sarraf M, et al. (1998) Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J. Clin. Oncol. 16:1310–7.CrossRefGoogle Scholar
  8. 8.
    Patel SG, Shah JP. (2005) TNM staging of cancers of the head and neck: striving for uniformity among diversity. CA Cancer J. Clin. 55:242–58; quiz 261–2, 264.CrossRefGoogle Scholar
  9. 9.
    Esteller M. (2008) Epigenetics in cancer. N. Engl. J. Med. 358:1148–59.CrossRefGoogle Scholar
  10. 10.
    Strahl BD, Allis CD. (2000) The language of covalent histone modifications. Nature. 403:41–45.CrossRefGoogle Scholar
  11. 11.
    Lund AH, van Lohuizen M. (2004) Epigenetics and cancer. Genes. Dev. 18:2315–35.CrossRefGoogle Scholar
  12. 12.
    Cao R, et al. (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 298:1039–43.CrossRefGoogle Scholar
  13. 13.
    Matsukawa Y, et al. (2006) Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci. 97:484–91.CrossRefGoogle Scholar
  14. 14.
    Mimori K, et al. (2005) Clinical significance of enhancer of zeste homolog 2 expression in colorectal cancer cases. Eur. J. Surg. Oncol. 31:376–80.CrossRefGoogle Scholar
  15. 15.
    Sudo T, et al. (2005) Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. British J. Cancer 92:1754–8.CrossRefGoogle Scholar
  16. 16.
    Collett K, et al. (2006) Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin. Cancer Res. 12:1168–74.CrossRefGoogle Scholar
  17. 17.
    Bachmann IM, et al. (2006) EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J. Clin. Oncol. 24:268–73.CrossRefGoogle Scholar
  18. 18.
    Kidani K, et al. (2009) High expression of EZH2 is associated with tumor proliferation and prognosis in human oral squamous cell carcinomas. Oral Oncology. 45:39–46.CrossRefGoogle Scholar
  19. 19.
    Raman JD, et al. (2005) Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin. Cancer Res. 11:8570–6.CrossRefGoogle Scholar
  20. 20.
    Varambally S, et al. (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 419:624–9.CrossRefGoogle Scholar
  21. 21.
    Yu J, et al. (2007) A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer Res. 67:10657–63.CrossRefGoogle Scholar
  22. 22.
    Wei Y, et al. (2008) Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancers. Mol. Carcinog. 47:701–6.CrossRefGoogle Scholar
  23. 23.
    Tzao C, et al. (2009) Prognostic significance of global histone modifications in resected squamous cell carcinoma of the esophagus. Mod. Pathol. 22:252–60.CrossRefGoogle Scholar
  24. 24.
    He LR, et al. (2009) Prognostic impact of H3K27me3 expression on locoregional progression after chemoradiotherapy in esophageal squamous cell carcinoma. BMC Cancer. 9:461.CrossRefGoogle Scholar
  25. 25.
    Lu TY, et al. (2009) DNA methylation and histone modification regulate silencing of OPG during tumor progression. J. Cell. Biochem. 108:315–25.CrossRefGoogle Scholar
  26. 26.
    Min H, et al. (1994) A new staging system for nasopharyngeal carcinoma in China. Int. J. Radiat. Oncol. Biol. Phys. 30:1037–42.CrossRefGoogle Scholar
  27. 27.
    Xie D, et al. (2003) Heterogeneous expression and association of beta-catenin, p16 and c-myc in multistage colorectal tumorigenesis and progression detected by tissue microarray. Int. J. Cancer 107:896–902.CrossRefGoogle Scholar
  28. 28.
    Cai MY, et al. Decreased expression of PinX1 protein is correlated with tumor development and is a new independent poor prognostic factor in ovarian carcinoma. Cancer Sci. 101:1543-9.CrossRefGoogle Scholar
  29. 29.
    Tong ZT, et al. (2011) EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin. Oncogene. (In press).Google Scholar
  30. 30.
    Lewis EB. (1978) A gene complex controlling segmentation in Drosophila. Nature. 276:565–70.CrossRefGoogle Scholar
  31. 31.
    Hansen KH, et al. (2008) A model for transmission of the H3K27me3 epigenetic mark. Nat. Cell. Biol 10:1291–300.CrossRefGoogle Scholar
  32. 32.
    Cai MY, et al. High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts patients worse prognosis. Mol. Med. 17:12-20.Google Scholar
  33. 33.
    Abbosh PH, et al. (2006) Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells. Cancer Res. 66:5582–91.CrossRefGoogle Scholar
  34. 34.
    Beyersmann J, Schumacher M. (2007) Misspecified regression model for the subdistribution hazard of a competing risk. Stat. Med. 26:1649–51.CrossRefGoogle Scholar
  35. 35.
    Cao R, Zhang Y. (2004) The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr. Opin. Genet. Dev. 14:155–64.CrossRefGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Mu-Yan Cai
    • 1
    • 2
  • Zhu-Ting Tong
    • 1
    • 4
  • Wei Zhu
    • 1
  • Zhu-Zhi Wen
    • 3
  • Hui-Lan Rao
    • 1
    • 2
  • Ling-Ling Kong
    • 4
  • Xin-Yuan Guan
    • 1
  • Hsiang-Fu Kung
    • 1
    • 5
  • Yi-Xin Zeng
    • 1
  • Dan Xie
    • 1
  1. 1.State Key Laboratory of Oncology in South China, Cancer CenterSun Yat-Sen UniversityGuangzhouChina
  2. 2.Department of Pathology, Cancer CenterSun Yat-Sen UniversityGuangzhouChina
  3. 3.Department of Cardiology, Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouChina
  4. 4.Department of Radiotherapy, the First Affiliated HospitalAnhui Medical UniversityHefeiChina
  5. 5.The State Key Laboratory of Oncology in South ChinaThe Chinese University of Hong KongShatinHong Kong, China

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