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Overexpression of Histone H3 Lysine 27 Trimethylation Is Associated with Aggressiveness and Dedifferentiation of Thyroid Cancer

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A variety of epigenetic dysregulations are observed in thyroid malignancies. EZH2, the catalytic subunit of polycomb repressive complex 2, is upregulated in advanced thyroid cancers. EZH2 can catalyze trimethylation of histone H3 at lysine 27 (H3K27me3) and contribute to transcriptional silencing of target genes. Here, we investigated the immunohistochemical expression of H3K27me3 in neoplastic and normal thyroid tissues. Normal thyroid epithelial cells typically exhibited nuclear staining of moderate intensity. A similar expression pattern was observed in nodular goiters and follicular adenomas. By contrast, strong H3K27me3 expression was evident in 80% (8/10) lymphocytic thyroiditis, 63% (80/127) papillary thyroid cancer, 41% (7/17) follicular thyroid cancer, and 73% (8/11) poorly differentiated and anaplastic thyroid cancer. In differentiated thyroid cancer, strong H3K27me3 expression was associated with extrathyroidal extension (p < 0.001), lymphovascular invasion (p = 0.029), lymph node metastasis (p = 0.006), and higher risk of recurrence (p = 0.003). Our results indicate that H3K27me3 overexpression may be implicated in aggressiveness and dedifferentiation of thyroid cancer. In addition to prognostication, the predictive value of H3K27me3 expression deserves further investigation given the recent development of epigenetic targeting agents.

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  1. 1.

    Asa SL, Ezzat S (2018) The epigenetic landscape of differentiated thyroid cancer. Mol Cell Endocrinol 469:3–10, DOI:

  2. 2.

    Yan KS, Lin CY, Liao TW, Peng CM, Lee SC, Liu YJ, Chan WP, Chou RH (2017) EZH2 in cancer progression and potential application in cancer therapy: a friend or foe? Int J Mol Sci 18:E1172.

  3. 3.

    Chien MN, Yang PS, Lee JJ, Wang TY, Hsu YC, Cheng SP (2017) Recurrence-associated genes in papillary thyroid cancer: An analysis of data from The Cancer Genome Atlas. Surgery 161:1642–1650, DOI:

  4. 4.

    Borbone E, Troncone G, Ferraro A, Jasencakova Z, Stojic L, Esposito F, Hornig N, Fusco A, Orlando V (2011) Enhancer of zeste homolog 2 overexpression has a role in the development of anaplastic thyroid carcinomas. J Clin Endocrinol Metab 96:1029–1038, DOI:

  5. 5.

    Kim KH, Roberts CW (2016) Targeting EZH2 in cancer. Nat Med 22:128–134, DOI:

  6. 6.

    Holm K, Grabau D, Lovgren K, Aradottir S, Gruvberger-Saal S, Howlin J, Saal LH, Ethier SP, Bendahl PO, Stal O, Malmstrom P, Ferno M, Ryden L, Hegardt C, Borg A, Ringner M (2012) Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes. Mol Oncol 6:494–506, DOI:

  7. 7.

    Wei Y, Xia W, Zhang Z, Liu J, Wang H, Adsay NV, Albarracin C, Yu D, Abbruzzese JL, Mills GB, Bast RC Jr, Hortobagyi GN, Hung MC (2008) Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancers. Mol Carcinog 47:701–706, DOI:

  8. 8.

    Schaefer IM, Fletcher CD, Hornick JL (2016) Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. Mod Pathol 29:4–13, DOI:

  9. 9.

    Lloyd RV, Osamura RY, Kloppel G, Rosai J (2017) WHO Classification of Tumours of Endocrine Organs, 4th edn. IARC, Lyon

  10. 10.

    Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A III (2010) AJCC cancer staging manual, 7th edn. Springer, New York

  11. 11.

    Cheng SP, Chien MN, Wang TY, Lee JJ, Lee CC, Liu CL (2018) Reconsideration of tumor size threshold for total thyroidectomy in differentiated thyroid cancer. Surgery 164:504–510, DOI:

  12. 12.

    Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L (2016) 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26:1–133, DOI:

  13. 13.

    Cheng SP, Hsu YC, Liu CL, Liu TP, Chien MN, Wang TY, Lee JJ (2014) Significance of allelic percentage of BRAF c.1799T > A (V600E) mutation in papillary thyroid carcinoma. Ann Surg Oncol 21 Suppl 4:S619-S626.

  14. 14.

    Lee JJ, Wang TY, Liu CL, Chien MN, Chen MJ, Hsu YC, Leung CH, Cheng SP (2017) Dipeptidyl peptidase IV as a prognostic marker and therapeutic target in papillary thyroid carcinoma. J Clin Endocrinol Metab 102:2930–2940, DOI:

  15. 15.

    Kampilafkos P, Melachrinou M, Kefalopoulou Z, Lakoumentas J, Sotiropoulou-Bonikou G (2015) Epigenetic modifications in cutaneous malignant melanoma: EZH2, H3K4me2, and H3K27me3 immunohistochemical expression is enhanced at the invasion front of the tumor. Am J Dermatopathol 37:138–144, DOI:

  16. 16.

    Liu CL, Yang PS, Chien MN, Chang YC, Lin CH, Cheng SP (2018) Expression of serine peptidase inhibitor Kunitz type 1 in differentiated thyroid cancer. Histochem Cell Biol 149:635–644, DOI:

  17. 17.

    Tuominen VJ, Ruotoistenmaki S, Viitanen A, Jumppanen M, Isola J (2010) ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67. Breast Cancer Res 12:R56.

  18. 18.

    Kijima T, Akai K, Nabika T, Taniguchi E, Matsushita A, Ishibashi Y (2018) Diagnostic difficulties and factors affecting diagnosis in acutely ill elderly Japanese patients living at home. Int J Gerontol 12:326–330, DOI:

  19. 19.

    Assenov Y, Brocks D, Gerhauser C (2018) Intratumor heterogeneity in epigenetic patterns. Semin Cancer Biol 51:12–21, DOI:

  20. 20.

    Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, Dogan S, Ricarte-Filho JC, Krishnamoorthy GP, Xu B, Schultz N, Berger MF, Sander C, Taylor BS, Ghossein R, Ganly I, Fagin JA (2016) Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest 126:1052–1066, DOI:

  21. 21.

    Masudo K, Suganuma N, Nakayama H, Oshima T, Rino Y, Iwasaki H, Matsuzu K, Sugino K, Ito K, Kondo T, Nakamura Y, Yoshihara M, Masuda M, Miyagi Y (2018) EZH2 overexpression as a useful prognostic marker for aggressive behaviour in thyroid cancer. In Vivo 32:25–31.

  22. 22.

    Barros-Filho MC, Marchi FA, Pinto CA, Rogatto SR, Kowalski LP. High diagnostic accuracy based on CLDN10, HMGA2, and LAMB3 transcripts in papillary thyroid carcinoma (2015) J Clin Endocrinol Metab 100:E890-E899, DOI:

  23. 23.

    Chien MN, Yang PS, Hsu YC, Liu TP, Lee JJ, Cheng SP (2018) Transcriptome analysis of papillary thyroid cancer harboring telomerase reverse transcriptase promoter mutation. Head Neck 40:2528–2537, DOI:

  24. 24.

    Gall Troselj K, Novak Kujundzic R, Ugarkovic D (2016) Polycomb repressive complex’s evolutionary conserved function: the role of EZH2 status and cellular background. Clin Epigenetics 8:55.

  25. 25.

    Nichol JN, Dupere-Richer D, Ezponda T, Licht JD, Miller WH Jr (2016) H3K27 methylation: a focal point of epigenetic deregulation in cancer. Adv Cancer Res 131:59–95.

  26. 26.

    Cheng SP, Chen MJ, Chien MN, Lin CH, Lee JJ, Liu CL (2017) Overexpression of teneurin transmembrane protein 1 is a potential marker of disease progression in papillary thyroid carcinoma. Clin Exp Med 17:555–564, DOI:

  27. 27.

    Cai MY, Hou JH, Rao HL, Luo RZ, Li M, Pei XQ, Lin MC, Guan XY, Kung HF, Zeng YX, Xie D (2011) High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts worse prognosis in patients. Mol Med 17:12–20, DOI:

  28. 28.

    Liu J, Li Y, Liao Y, Mai S, Zhang Z, Liu Z, Jiang L, Zeng Y, Zhou F, Xie D (2013) High expression of H3K27me3 is an independent predictor of worse outcome in patients with urothelial carcinoma of bladder treated with radical cystectomy. Biomed Res Int 2013:390482, DOI:

  29. 29.

    Chen YW, Kao SY, Wang HJ, Yang MH (2013) Histone modification patterns correlate with patient outcome in oral squamous cell carcinoma. Cancer 119:4259–4267, DOI:

  30. 30.

    He LR, Liu MZ, Li BK, Rao HL, Liao YJ, Guan XY, Zeng YX, Xie D (2009) Prognostic impact of H3K27me3 expression on locoregional progression after chemoradiotherapy in esophageal squamous cell carcinoma. BMC Cancer 9:461.

  31. 31.

    Schaefer IM, Minkovsky A, Hornick JL (2016) H3K27me3 immunohistochemistry highlights the inactivated X chromosome (Xi) and predicts sex in non-neoplastic tissues. Histopathology 69:702–704, DOI:

  32. 32.

    Iannetti A, Ledoux AC, Tudhope SJ, Sellier H, Zhao B, Mowla S, Moore A, Hummerich H, Gewurz BE, Cockell SJ, Jat PS, Willmore E, Perkins ND (2014) Regulation of p53 and Rb links the alternative NF-κB pathway to EZH2 expression and cell senescence. PLoS Genet 10:e1004642, DOI:

  33. 33.

    Qu Y, Yang Q, Liu J, Shi B, Ji M, Li G, Hou P (2017) c-Myc is required for BRAF V600E-induced epigenetic silencing by H3K27me3 in tumorigenesis. Theranostics 7:2092–2107, DOI:

  34. 34.

    Rothenberg SM, McFadden DG, Palmer EL, Daniels GH, Wirth LJ (2015) Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res 21:1028–1035, DOI:

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This work was supported by research grants from the Ministry of Science and Technology of Taiwan (MOST-107-2314-B-195-001-MY3) and MacKay Memorial Hospital (MMH-10813 and MMH-E-108-10). The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

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Correspondence to Shih-Ping Cheng.

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The authors declare that they have no conflict of interest.

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The study was approved by the Institutional Review Board of MacKay Memorial Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of MacKay Memorial Hospital and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

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Tsai, C., Chien, M., Chang, Y. et al. Overexpression of Histone H3 Lysine 27 Trimethylation Is Associated with Aggressiveness and Dedifferentiation of Thyroid Cancer. Endocr Pathol 30, 305–311 (2019).

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  • H3K27me3
  • EZH2
  • Thyroid cancer
  • Immunohistochemistry