lncRNA MALAT1 binds chromatin remodeling subunit BRG1 to epigenetically promote inflammation-related hepatocellular carcinoma progression
lncRNA MALAT1 binds chromatin remodeling subunit BRG1 to epigenetically promote inflammation-related hepatocellular carcinoma progression
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DOI：
10.1080/2162402x.2018.1518628
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发表时间：
2019-01-01
期刊：
影响因子：
7.2
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Huang, Mingyan;Wang, Huamin;Cao, Xuetao
肝细胞癌（Hepatocellular carcinoma，HCC）是一种与慢性炎症密切相关的恶性肿瘤。确定炎症相关HCC进展的分子机制将有助于提高目前HCC患者治疗的疗效。目前已发现多种表观遗传因子，包括长链非编码RNA（lncRNA），在肝癌的生长和转移中起重要作用。然而，lncRNA如何促进肝癌的进展以及lncRNA沉默在体内抑制肝癌的应用仍有待进一步研究。在此，我们发现lncRNA转移相关肺腺癌转录物1（MALAT 1）在HCC肿瘤组织中上调，并且MALAT 1的敲低抑制了HCC细胞对脂多糖（LPS）刺激的增殖、细胞周期和侵袭。MALAT 1的敲低显著抑制了HCC细胞中LPS诱导的促炎介质IL-6和CXCL 8的表达，这可以通过过表达MALAT 1来恢复。机制上，MALAT 1将Brahma相关基因1（BRG 1）（染色质重塑复合物转换/蔗糖非发酵（SWI/SNF）的催化亚基）募集到IL-6和CXCL 8的启动子区，从而促进NF-κ B诱导这些炎性因子的表达。重要的是，HCC组织中MALAT 1的体内沉默抑制HCC异种移植物的生长，并且还相应地抑制HCC组织中促炎因子的表达。我们的研究结果表明，MALAT 1通过结合BRG 1促进HCC进展，从而在HCC组织中表观遗传地增强炎症反应，并且MALAT 1的沉默可能是治疗HCC的潜在方法。
Hepatocellular carcinoma (HCC) is one type of cancers whose carcinogenesis and progression are closely related to chronic inflammation. Identifying the molecular mechanisms for inflammation-related HCC progression will contribute to improve the efficacy of current therapeutics for HCC patients. Many kinds of epigenetic factors, including long non-coding RNAs (lncRNAs), have been discovered to be important in HCC growth and metastasis. However, how the lncRNAs promote HCC progression and what's the application of lncRNA silencing in vivo in suppressing HCC remain to be further investigated. Here, we found that lncRNA metastasis associated lung adenocarcinoma transcript1 (MALAT1) was upregulated in HCC tumor tissues, and knockdown of MALAT1 suppressed proliferation, cell cycle and invasion of HCC cells in response to lipopolysaccharide (LPS) stimulation. Knockdown of MALAT1 significantly inhibited LPS-induced pro-inflammatory mediators IL-6 and CXCL8 expression in HCC cells, which could be restored by overexpressing MALAT1. Mechanistically, MALAT1 recruited Brahma-related gene 1 (BRG1), a catalytic subunit of chromatin remodeling complex switching/sucrose non-fermentable (SWI/SNF), to the promoter region of IL-6 and CXCL8, and thus facilitated NF-kappa B to induce the expression of these inflammatory factors. Importantly, in vivo silencing of MALAT1 in HCC tissues inhibited growth of HCC xenografts, and also suppressed the expression of pro-inflammatory factors in HCC tissues accordingly. Our results demonstrate that MALAT1 promotes HCC progression by binding BRG1 to epigenetically enhance inflammatory response in HCC tissues, and silencing of MALAT1 may be a potential approach to the treatment of HCC.