HOTAIR promotes gefitinib resistance through modification of EZH2 and silencing p16 and p21 in non-small cell lung cancer.
HOTAIR promotes gefitinib resistance through modification of EZH2 and silencing p16 and p21 in non-small cell lung cancer.
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HOTAIR 通过修饰 EZH2 和沉默 p16 和 p21 在非小细胞肺癌中促进吉非替尼耐药
DOI：
10.7150/jca.56093
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发表时间：
2021
影响因子：
3.9
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Li W;Li Y;Zhang H;Liu M;Gong H;Yuan Y;Shi R;Zhang Z;Liu C;Chen C;Liu H;Chen J
长非编码RNA HOX转录本反义基因间RNA(HOTAIR)在多种肿瘤的发生和耐药中起重要作用。然而，HOTAIR诱导非小细胞肺癌对吉非替尼耐药的分子机制迄今尚不清楚。在目前的研究中，我们发现HOTAIR在对吉非替尼耐药的肺癌细胞中上调，并且HOTAIR的过表达增强了肺癌细胞对吉非替尼的耐药性。此外，HOTAIR的过表达通过对EZH2/H3K27的表观遗传调控促进了细胞周期的进展。通过siRNA或抑制剂沉默EZH2使肺癌细胞对吉非替尼敏感。在高表达HOTAIR的PC-9细胞中，抑制EZH2可诱导p16和p21的表达，而CDK4、细胞周期蛋白D1、E2F1和LSD1的表达水平显著降低。芯片-聚合酶链式反应实验表明，在高表达HOTAIR的PC-9肺癌细胞中，HOTAIR增加了H3K27me3对p16和p21启动子的募集。在异种移植小鼠模型中，肺癌组织中HOTAIR的过度表达降低了p16和p21蛋白。综上所述，这些数据表明HOTAIR通过调节EZH2、p16和p21而导致吉非替尼耐药。靶向HOTAIR可能是治疗非小细胞肺癌吉非替尼耐药的新策略。
The long non-coding RNA Hox transcript antisense intergenic RNA (HOTAIR) plays a critical role in tumorigenesis as well as drug resistance in various cancers. However, the molecular mechanism by which HOTAIR induces gefitinib resistance in non-small cell lung cancer is to date unclear. In the present study, we revealed that HOTAIR is upregulated in gefitinib-resistant lung cancer cells and over-expression of HOTAIR enhances gefitinib resistance in lung cancer cells. In addition, the overexpression of HOTAIR promotes cell cycle progression through epigenetic regulation of EZH2/H3K27. Silencing of EZH2 by either siRNA or inhibitors sensitized the lung cancer cells to gefitinib. Inhibition of EZH2 induces expression of p16 and p21, whereas levels of CDK4, cyclinD1, E2F1, and LSD1 are significantly decreased in PC-9 cells overexpressing HOTAIR. ChIP-PCR experiments indicate that HOTAIR increases H3K27me3 recruitment to the promoter of p16 and p21 in PC-9 lung cancer cells overexpressing HOTAIR. In xenograft mouse models, overexpressing HOTAIR in lung cancer tissues decreased p16 and p21 proteins. Taken together, these data suggest that HOTAIR contributes to gefitinib resistance by regulating EZH2 and p16 and p21. Targeting HOTAIR may be a novel therapeutic strategy for treating gefitinib-resistance in non-small cell lung cancer.