Wang Chenyu, Li Xingwang, Zhang Junjie, Ge Zheng, Chen Hejin, Hu Junhong
Department of Anorectal, Huaihe Hospital of Henan University, Kaifeng, 475000, People's Republic of China,
Onco Targets Ther. 2018 Nov 5;11:7853-7864. doi: 10.2147/OTT.S180131. eCollection 2018.
Increasing evidence suggests the involvement of enhancer of zeste homologue 2 (EZH2) in chemoresistance of cancer treatment. Nevertheless, its function and molecular mechanisms in gastric cancer (GC) chemoresistance are still not well elucidated.
In the present study, we investigated the functional role of EZH2 in 5-fluorouracil (5-FU) resistance of GC cells and discovered the underlying molecular mechanism.
Results revealed that EZH2 was upregulated in 5-FU-resistant GC tissues and cell lines. High ZEH2 expression was correlated with poor prognosis of GC patients. EZH2 knockdown enhanced 5-FU sensitivity of AGS/5-FU and SGC-7901/5-FU cells. Moreover, EZH2 could epigenetically suppress FBXO32 expression. FBXO32 overexpression could mimic the functional role of downregulated EZH2 in 5-FU resistance. FBXO32 knockdown counteracted the inductive effect of EZH2 inhibition on 5-FU sensitivity of AGS/5-FU and SGC-7901/5-FU cells. Furthermore, EZH2 knockdown facilitated 5-FU sensitivity of 5-FU-resistant GC cells in vivo.
In summary, EZH2 depletion overcame 5-FU resistance in GC by epigenetically silencing FBXO32, providing a novel therapeutic target for GC chemoresistance.
越来越多的证据表明，zeste同源物2增强子（EZH2）参与癌症治疗的化疗耐药性。然而，其在胃癌（GC）化疗耐药中的功能和分子机制仍未得到充分阐明。
在本研究中，我们研究了EZH2在GC细胞对5-氟尿嘧啶（5-FU）耐药中的功能作用，并发现了潜在的分子机制。
结果显示，EZH2在5-FU耐药的GC组织和细胞系中上调。ZEH2高表达与GC患者的不良预后相关。EZH2敲低增强了AGS/5-FU和SGC-7901/5-FU细胞对5-FU的敏感性。此外，EZH2可通过表观遗传方式抑制FBXO32的表达。FBXO32过表达可模拟下调EZH2在5-FU耐药中的功能作用。FBXO32敲低抵消了EZH2抑制对AGS/5-FU和SGC-7901/5-FU细胞5-FU敏感性的诱导作用。此外，EZH2敲低促进了体内5-FU耐药GC细胞对5-FU的敏感性。
总之，EZH2缺失通过表观遗传沉默FBXO32克服了GC中的5-FU耐药性，为GC化疗耐药提供了一个新的治疗靶点。
