The polycomb group protein enhancer of zeste 2 is a novel therapeutic target for cervical cancer
The polycomb group protein enhancer of zeste 2 is a novel therapeutic target for cervical cancer
复制标题
DOI：
10.1111/1440-1681.12382
复制
发表时间：
2015-05-01
影响因子：
2.9
通讯作者：
Gao, Yane
中科院分区：
文献类型：
--
作者：
Ding, Muyang;Zhang, Hang;Gao, Yane
Zeste 2增强子（EZH 2）是一种多梳型组蛋白甲基转移酶，在包括宫颈癌在内的各种癌症中过表达。基因表达分析显示，EZH 2的表达增加与宫颈癌进展相关，特别是向浸润性鳞状细胞癌的进展。已知zeste 2的增强子使组蛋白H3上的赖氨酸27三甲基化，导致基因沉默，这有助于肿瘤进展为更具侵袭性的癌症形式。然而，EZH 2促进宫颈癌发展的具体分子机制在很大程度上仍然未知。最近，据报道，EZH 2抑制剂选择性地抑制组蛋白H3上的三甲基化赖氨酸27并重新激活癌细胞中沉默的基因。在这项研究中，我们发现GSK 343（EZH 2甲基转移酶的特异性抑制剂）诱导癌细胞从间充质细胞到上皮细胞的表型重编程，降低增殖和细胞运动性，并在体外和体内阻断宫颈癌细胞系的侵袭。用EZH 2抑制剂治疗导致上皮标志物E-钙粘蛋白水平增加和间充质标志物如N-钙粘蛋白和波形蛋白水平降低。观察到的重编程与宫颈癌进展受限相关，并提供了支持EZH 2作为治疗靶点的直接证据。
Enhancer of zeste 2 (EZH2), a polycomb histone methyltransferase, is overexpressed in various cancers, including cervical cancer. Gene expression analysis revealed that increased expression of EZH2 is associated with cervical cancer progression, particularly the progression to invasive squamous cell carcinoma. Enhancer of zeste 2 is known to trimethylate lysine 27 on histone H3, leading to gene silencing that contributes to the progression of tumours into a more aggressive form of cancer. However, the specific molecular mechanisms by which EZH2 contributes to the development of cervical cancer remain largely unknown. Recently, an EZH2 inhibitor was reported to selectively inhibit trimethylated lysine 27 on histone H3 and to reactivate silenced genes in cancer cells. In this study, we found that GSK343 (a specific inhibitor of EZH2 methyltransferase) induces phenotypic reprogramming of cancer cells from mesenchymal to epithelial cells, reducing proliferation and cell motility and blocking the invasion of cervical cancer cell lines both in vitro and in vivo. Treatment with the EZH2 inhibitor led to increased levels of the epithelial marker E-cadherin and decreased levels of mesenchymal markers such as N-cadherin and vimentin. The observed reprogramming is associated with restrained cervical cancer progression and provides direct evidence in support of EZH2 as a therapeutic target.