Song Yue, Wang Rui, Li Li-Wei, Liu Xi, Wang Yun-Fei, Wang Qi-Xue, Zhang Qingyu
Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, P.R. China.
Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
Int J Oncol. 2019 Jan;54(1):77-86. doi: 10.3892/ijo.2018.4625. Epub 2018 Nov 5.
HOX transcript antisense intergenic RNA (HOTAIR), a well‑known long non‑coding RNA, plays an important role in the regulation of epithelial‑to‑mesenchymal transition (EMT). In this study, we propose a novel mechanism through which HOTAIR promotes EMT by switching histone H3 lysine 27 acetylation to methylation at the E‑cadherin promoter, which induces the transcriptional inhibition of E‑cadherin. HOTAIR recruits polycomb repressive complex 2 (PRC2) to catalyze H3K27me3; however, whether HOTAIR is associated with the acetylation of histone H3 lysine 27, a marker of transcriptional activation, and the mechanisms through which HOTAIR triggers the metastasis of gastric cancer (GC) by epigenetic regulation remain largely unknown. In this study, HOTAIR knockdown significantly reversed EMT by increasing the expression of E‑cadherin in GC cells. Additionally, the loss of PRC2 activity induced by HOTAIR knockdown resulted in a global decrease in H3K27 methylation and an increase in H3K27 acetylation. Furthermore, HOTAIR recruits PRC2 (which consists of H3K27 methyltransferase EZH2, SUZ12 and EED), which may inhibit the reaction between the acetyltransferase CBP and H3K27 acetylation. On the whole, the findings of this study suggested that the HOTAIR‑mediated acetylation to methylation switch was associated with the transcriptional inhibition of E‑cadherin. HOTAIR can promote the development of GC through the epigenetic regulation of E‑cadherin, switching the state of the E‑cadherin promoter from the transcriptionally active to the transcriptionally repressive state.
HOX转录本反义基因间RNA（HOTAIR）是一种著名的长链非编码RNA，在上皮-间质转化（EMT）的调控中发挥重要作用。在本研究中，我们提出了一种新机制，即HOTAIR通过将E-钙黏蛋白启动子上组蛋白H3赖氨酸27的乙酰化转换为甲基化来促进EMT，这会诱导E-钙黏蛋白的转录抑制。HOTAIR招募多梳抑制复合物2（PRC2）来催化H3K27me3；然而，HOTAIR是否与转录激活标记物组蛋白H3赖氨酸27的乙酰化相关，以及HOTAIR通过表观遗传调控触发胃癌（GC）转移的机制在很大程度上仍不清楚。在本研究中，HOTAIR敲低通过增加GC细胞中E-钙黏蛋白的表达显著逆转了EMT。此外，HOTAIR敲低诱导的PRC2活性丧失导致H3K27甲基化整体减少和H3K27乙酰化增加。此外，HOTAIR招募PRC2（其由H3K27甲基转移酶EZH2、SUZ12和EED组成），这可能抑制乙酰转移酶CBP与H3K27乙酰化之间的反应。总体而言，本研究结果表明，HOTAIR介导的乙酰化到甲基化的转换与E-钙黏蛋白的转录抑制相关。HOTAIR可通过对E-钙黏蛋白的表观遗传调控促进GC的发展，将E-钙黏蛋白启动子的状态从转录活性状态转变为转录抑制状态。
