EZH2-mediated epigenetic suppression of long noncoding RNA SPRY4-IT1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial-mesenchymal transition.
EZH2-mediated epigenetic suppression of long noncoding RNA SPRY4-IT1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial-mesenchymal transition.
复制标题
EZH2介导的长非编码RNA SPRY4-IT1的表观遗传抑制通过影响上皮间质转化促进NSCLC细胞增殖和转移
DOI：
10.1038/cddis.2014.256
复制
发表时间：
2014-06-26
影响因子：
9
通讯作者：
Wang ZX
中科院分区：
文献类型：
--
作者：
Sun M;Liu XH;Lu KH;Nie FQ;Xia R;Kong R;Yang JS;Xu TP;Liu YW;Zou YF;Lu BB;Yin R;Zhang EB;Xu L;De W;Wang ZX
最近的证据表明，长链非编码RNA（lncRNA）在细胞过程如分化，增殖和转移的调节中具有关键作用。这些lncRNA在多种癌症中失调，并且许多起肿瘤抑制剂的作用;然而，参与沉默lncRNA转录的调节因子知之甚少。在这项研究中，我们发现lncRNA SPRY 4内含子转录本1（SPRY 4-IT 1）的表观遗传沉默发生在非小细胞肺癌（NSCLC）细胞中，通过由Polycomb组蛋白增强子zeste同源物2（EZH 2）介导的直接转录抑制。SPRY 4-IT 1来源于SPRY 4内的内含子，并且在黑素瘤细胞中上调;其表达的敲低导致细胞生长停滞、侵袭抑制和凋亡率升高。在通过RNA干扰耗尽EZH 2后，SPRY 4-IT 1表达恢复，并且SPRY 4-IT 1转染到NSCLC细胞中在培养物和异种移植裸鼠中均产生显著的抗肿瘤作用。此外，SPRY 4-IT 1的过表达被发现通过调节E-钙粘蛋白和波形蛋白的表达在上皮-间充质转化中发挥关键作用。在EZH 2敲除细胞中，其特征性地显示受损的细胞增殖和转移，SPRY 4-IT 1耗尽的诱导部分地挽救了致癌表型，表明SPRY 4-IT 1抑制在EZH 2肿瘤发生中具有重要作用。最相关的是，将这些发现转化为人类NSCLC组织样本表明，SPRY 4-IT 1表达水平低的患者的总生存时间较短，这表明SPRY 4-IT 1可能是NSCLC预后不良的生物标志物。
Recent evidence indicates that long noncoding RNAs (lncRNAs) have a critical role in the regulation of cellular processes such as differentiation, proliferation, and metastasis. These lncRNAs are dysregulated in a variety of cancers and many function as tumor suppressors; however, the regulatory factors involved in silencing lncRNA transcription are poorly understood. In this study, we showed that epigenetic silencing of lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) occurs in non-small-cell lung cancer (NSCLC) cells through direct transcriptional repression mediated by the Polycomb group protein enhancer of zeste homolog 2 (EZH2). SPRY4-IT1 is derived from an intron within SPRY4, and is upregulated in melanoma cells; knockdown of its expression leads to cell growth arrest, invasion inhibition, and elevated rates of apoptosis. Upon depletion of EZH2 by RNA interference, SPRY4-IT1 expression was restored, and transfection of SPRY4-IT1 into NSCLC cells resulted in a significant antitumoral effect, both in culture and in xenografted nude mice. Moreover, overexpression of SPRY4-IT1 was found to have a key role in the epithelial–mesenchymal transition through the regulation of E-cadherin and vimentin expression. In EZH2-knockdown cells, which characteristically showed impaired cell proliferation and metastasis, the induction of SPRY4-IT1 depletion partially rescued the oncogenic phenotype, suggesting that SPRY4-IT1 repression has an important role in EZH2 oncogenesis. Of most relevance, translation of these findings into human NSCLC tissue samples demonstrated that patients with low levels of SPRY4-IT1 expression had a shorter overall survival time, suggesting that SPRY4-IT1 could be a biomarker for poor prognosis of NSCLC.