Targeting EZH2 as a novel therapeutic strategy for sorafenib-resistant thyroid carcinoma

J Cell Mol Med. 2019 Jul;23(7):4770-4778. doi: 10.1111/jcmm.14365. Epub 2019 May 13.


Thyroid carcinoma is the most common endocrine malignancy. Surgery, post-operative selective iodine-131 and thyroid hormone suppression were the most common methods for the therapy of thyroid carcinoma. Although most patients with differentiated thyroid carcinoma (DTC) showed positive response for these therapeutic methods, some patients still have to face the radioactive iodine (RAI)-refractory problems. Sorafenib is an oral multikinase inhibitor for patients with advanced RAI refractory DTC. However, the side effects and drug resistance of sorafenib suggest us to develop novel drugs and strategies for the therapy of thyroid carcinoma. In this study, we firstly found that patients with sorafenib resistance showed no significant change in rapidly accelerated fibrosarcoma and VEGFR expression levels compared with sorafenib sensitive patients. Moreover, a further miRNAs screen by qRT-PCR indicated that miR-124-3p and miR-506-3p (miR-124/506) were remarkably reduced in sorafenib insensitive patients. With a bioinformatics prediction and functional assay validation, we revealed that enhancer of zeste homolog 2 (EZH2) was the direct target for miR-124/506. Interestingly, we finally proved that the sorafenib resistant cells regained sensitivity for sorafenib by EZH2 intervention with miR-124/506 overexpression or EZH2 inhibitor treatment in vitro and in vivo, which will lead to the decreased tri-methylation at lysine 27 of histone H3 (H3K27me3) and increased acetylated lysine 27 of histone H3 (H3K27ac) levels. Therefore, we conclude that the suppression of EZH2 represents a potential target for thyroid carcinoma therapy.

Keywords: EZH2; H3K27; Sorafenib; miR-124/506; thyroid carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Epigenesis, Genetic / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Molecular Targeted Therapy*
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Sorafenib / pharmacology*
  • Survival Analysis
  • Thyroid Neoplasms / blood
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / metabolism*


  • MIRN124 microRNA, human
  • MIRN506 microRNA, human
  • MicroRNAs
  • Sorafenib
  • Enhancer of Zeste Homolog 2 Protein
  • Receptors, Vascular Endothelial Growth Factor