Li Weiting, Li Yongwen, Zhang Hongbing, Liu Minghui, Gong Hao, Yuan Yin, Shi Ruifeng, Zhang Zihe, Liu Chao, Chen Chen, Liu Hongyu, Chen Jun
Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
J Cancer. 2021 Jul 25;12(18):5562-5572. doi: 10.7150/jca.56093. eCollection 2021.
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.
长链非编码RNA Hox转录反义基因间RNA（HOTAIR）在多种癌症的肿瘤发生以及耐药性中发挥着关键作用。然而，迄今为止，HOTAIR在非小细胞肺癌中诱导吉非替尼耐药的分子机制尚不清楚。在本研究中，我们发现HOTAIR在吉非替尼耐药的肺癌细胞中上调，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EZH2/H3K27的表观遗传调控促进细胞周期进程。通过siRNA或抑制剂使EZH2沉默可使肺癌细胞对吉非替尼敏感。抑制EZH2可诱导p16和p21的表达，而在过表达HOTAIR的PC-9细胞中，CDK4、细胞周期蛋白D1、E2F1和LSD1的水平显著降低。染色质免疫沉淀-聚合酶链反应（ChIP-PCR）实验表明，在过表达HOTAIR的PC-9肺癌细胞中，HOTAIR增加了H3K27me3募集到p16和p21启动子上。在异种移植小鼠模型中，肺癌组织中过表达HOTAIR会降低p16和p21蛋白水平。综上所述，这些数据表明HOTAIR通过调节EZH2以及p16和p21促成吉非替尼耐药。靶向HOTAIR可能是治疗非小细胞肺癌吉非替尼耐药的一种新的治疗策略。
