Open AccessTargeting EZH 2 as a novel therapeutic strategy for sorafenib‐resistant thyroid carcinoma
Author(s) -
Wang Zhengshi,
Dai Jiaqi,
Yan Jie,
Zhang Yun,
Yin Zhiqiang
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14365
Subject(s) - sorafenib , thyroid carcinoma , ezh2 , cancer research , medicine , thyroid , thyroid cancer , sunitinib , oncology , malignancy , carcinoma , endocrinology , methylation , cancer , hepatocellular carcinoma , chemistry , biochemistry , gene
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 mi RNA s 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 ( EZH 2) was the direct target for miR‐124/506. Interestingly, we finally proved that the sorafenib resistant cells regained sensitivity for sorafenib by EZH 2 intervention with miR‐124/506 overexpression or EZH 2 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 EZH 2 represents a potential target for thyroid carcinoma therapy.