Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells
Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells
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DOI：
10.1038/labinvest.2015.123
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发表时间：
2016-01-01
影响因子：
5
通讯作者：
Guo, Linlang
中科院分区：
文献类型：
--
作者：
Fang, Shun;Gao, Hongyi;Guo, Linlang
同源异型框（HOX）转录反义RNA（HOTAIR）是一种长的基因间非编码RNA（lincRNA），在包括小细胞肺癌（SCLC）在内的多种肿瘤中发挥致癌作用。然而，尚不清楚HOTAIR是否可以调节SCLC的化疗耐药性。本研究的目的是探讨HOTAIR在SCLC化疗耐药性中的作用及其可能的分子机制。在SCLC多药耐药细胞系（H69 AR和H446 AR）和亲本细胞系（H69和H446）中进行HOTAIR的敲低以评估其对化学抗性的影响。结果表明，HOTAIR的下调通过增加细胞凋亡和细胞周期阻滞增加细胞对抗癌药物的敏感性，并抑制体内肿瘤生长。此外，使用亚硫酸氢盐测序PCR，HOXA 1甲基化在耐药细胞中增加。HOTAIR的耗竭通过降低DNMT 1和DNMT 3b表达来降低HOXA 1甲基化。通过RNA免疫沉淀验证HOTAIR和HOXA 1之间的相互作用。综上所述，我们的研究表明HOTAIR通过调节HOXA 1甲基化介导SCLC的化疗耐药性，并可用作新的化疗耐药性辅助治疗的潜在靶点。
Homeobox (HOX) transcript antisense RNA (HOTAIR), a long intergenic noncoding RNA (lincRNA), has been reported to play an oncogenic role in various cancers including small cell lung cancer (SCLC). However, it is not known whether HOTAIR can modulate chemoresistance in SCLC. The aim of this study is to investigate the roles of HOTAIR in chemoresistance of SCLC and its possible molecular mechanism. Knockdown of HOTAIR was carried out in SCLC multidrug-resistant cell lines (H69AR and H446AR) and the parental cell lines (H69 and H446) to assess its influence on chemoresistance. The results showed that downregulation of HOTAIR increased cell sensitivity to anticancer drugs through increasing cell apoptosis and cell cycle arrest, and suppressed tumor growth in vivo. Moreover, HOXA1 methylation increased in the resistant cells using bisulfite sequencing PCR. Depletion of HOTAIR reduced HOXA1 methylation by decreasing DNMT1 and DNMT3b expression. The interaction between HOTAIR and HOXA1 was validated by RNA immunoprecipitation. Taken together, our study suggested that HOTAIR mediates chemoresistance of SCLC by regulating HOXA1 methylation and could be utilized as a potential target for new adjuvant therapies against chemoresistance.