J Cancer 2021; 12(18):5562-5572. doi:10.7150/jca.56093 This issue

Research Paper

HOTAIR promotes gefitinib resistance through modification of EZH2 and silencing p16 and p21 in non-small cell lung cancer

Weiting Li1#, Yongwen Li2#, Hongbing Zhang1#, Minghui Liu1, Hao Gong1, Yin Yuan1, Ruifeng Shi1, Zihe Zhang1, Chao Liu1, Chen Chen2, Hongyu Liu2✉, Jun Chen1,2✉

1. Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
2. Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
#These authors contributed equally in this work.

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Citation:
Li W, Li Y, Zhang H, Liu M, Gong H, Yuan Y, Shi R, Zhang Z, Liu C, Chen C, Liu H, Chen J. HOTAIR promotes gefitinib resistance through modification of EZH2 and silencing p16 and p21 in non-small cell lung cancer. J Cancer 2021; 12(18):5562-5572. doi:10.7150/jca.56093. Available from https://www.jcancer.org/v12p5562.htm

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Abstract

Graphic abstract

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.

Keywords: Lung cancer, HOTAIR, Gefitinib resistance, EZH2