RNA helicase DEAD box protein 5 regulates Polycomb repressive complex 2/Hox transcript antisense intergenic RNA function in hepatitis B virus infection and hepatocarcinogenesis.
RNA helicase DEAD box protein 5 regulates Polycomb repressive complex 2/Hox transcript antisense intergenic RNA function in hepatitis B virus infection and hepatocarcinogenesis.
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DOI：
10.1002/hep.28698
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发表时间：
2016-10
期刊：
影响因子：
13.5
通讯作者：
Andrisani, Ourania
中科院分区：
文献类型：
--
作者：
Zhang, Hao;Xing, Zheng;Mani, Saravana Kumar Kailasam;Bancel, Brigitte;Durantel, David;Zoulim, Fabien;Tran, Elizabeth J.;Merle, Philippe;Andrisani, Ourania
慢性乙型肝炎病毒 (HBV) 感染是肝细胞癌 (HCC) 发病机制的主要因素，其机制尚不清楚。需要阐明 HBV 介导的肝癌发生机制，以深入了解 HCC 的分类和治疗。在 HBV 复制细胞中，包括病毒相关的 HCC，zeste 12 同源物抑制因子 (SUZ12)（Polycomb 抑制复合物 2 (PRC2) 的核心亚基）会经历蛋白酶体降解。这个过程需要长非编码RNA，Hox转录反义基因间RNA（HOTAIR）。有趣的是，HOTAIR 与 PRC2 相互作用，还结合 RNA 结合 E3 连接酶，充当泛素化支架。在此，我们确定了 RNA 解旋酶 DEAD box 蛋白 5 (DDX5) 作为 SUZ12 稳定性和 PRC2 介导的基因抑制的调节剂，通过调节与 HOTAIR 形成的 RNA-蛋白复合物发挥作用。具体来说，DDX5 和/或 HOTAIR 的敲除使 PRC2 抑制的基因上皮细胞粘附分子 (EpCAM) 和多能性基因重新表达。此外，DDX5 的敲除增强了 HBV 微型染色体的转录。 DDX5 的解旋酶活性通过取代 HOTAIR 的 RNA 结合 E3 连接酶、Mex-3 RNA 结合家族成员 B (Mex3b) 稳定 SUZ12 和 PRC2 介导的基因沉默。相反，Mex3b 的异位表达使 SUZ12 泛素化，从 HOTAIR 中取代 DDX5，并诱导 SUZ12 下调。在表达 HBV X 蛋白 (HBx) 的细胞的 G2 期，SUZ12 优先与 Mex3b 而不是 DDX5 相关，从而导致 PRC2 靶标（包括 EpCAM 和多能性基因）的去抑制。值得注意的是，HBx/c-myc 双转基因小鼠和慢性 HBV 感染患者的肝肿瘤在 DDX5 信使 RNA 水平、多能性基因表达和肝肿瘤分化之间表现出强烈的负相关。值得注意的是，慢性感染 HBV 且 DDX5 表达减少的 HCC 患者在肿瘤切除后表现出不良预后，表明 DDX5 是不良预后 HCC 的重要参与者。结论：RNA 解旋酶 DDX5 和 E3 连接酶 Mex3b 是设计新型表观遗传疗法以对抗 HBV 感染和预后不良的 HBV 相关肝癌的重要细胞靶标。 （肝病学 2016；64：1033‐1048）
Chronic hepatitis B virus (HBV) infection is a major factor in hepatocellular carcinoma (HCC) pathogenesis by a mechanism not yet understood. Elucidating mechanisms of HBV‐mediated hepatocarcinogenesis is needed to gain insights into classification and treatment of HCC. In HBV replicating cells, including virus‐associated HCCs, suppressor of zeste 12 homolog (SUZ12), a core subunit of Polycomb repressive complex2 (PRC2), undergoes proteasomal degradation. This process requires the long noncoding RNA, Hox transcript antisense intergenic RNA (HOTAIR). Intriguingly, HOTAIR interacts with PRC2 and also binds RNA‐binding E3 ligases, serving as a ubiquitination scaffold. Herein, we identified the RNA helicase, DEAD box protein 5 (DDX5), as a regulator of SUZ12 stability and PRC2‐mediated gene repression, acting by regulating RNA‐protein complexes formed with HOTAIR. Specifically, knockdown of DDX5 and/or HOTAIR enabled reexpression of PRC2‐repressed genes epithelial cell adhesion molecule (EpCAM) and pluripotency genes. Also, knockdown of DDX5 enhanced transcription from the HBV minichromosome. The helicase activity of DDX5 stabilized SUZ12‐ and PRC2‐mediated gene silencing, by displacing the RNA‐binding E3 ligase, Mex‐3 RNA‐binding family member B (Mex3b), from HOTAIR. Conversely, ectopic expression of Mex3b ubiquitinated SUZ12, displaced DDX5 from HOTAIR, and induced SUZ12 down‐regulation. In G2 phase of cells expressing the HBV X protein (HBx), SUZ12 preferentially associated with Mex3b, but not DDX5, resulting in de‐repression of PRC2 targets, including EpCAM and pluripotency genes. Significantly, liver tumors from HBx/c‐myc bitransgenic mice and chronically HBV‐infected patients exhibited a strong negative correlation between DDX5 messenger RNA levels, pluripotency gene expression, and liver tumor differentiation. Notably, chronically infected HBV patients with HCC expressing reduced DDX5 exhibited poor prognosis after tumor resection, identifying DDX5 as an important player in poor prognosis HCC. Conclusion: The RNA helicase DDX5, and E3 ligase Mex3b, are important cellular targets for the design of novel, epigenetic therapies to combat HBV infection and poor prognosis HBV‐associated liver cancer. (Hepatology 2016;64:1033‐1048)
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影响因子：
16
作者：
Cifuentes-Rojas, Catherine;Hernandez, Alfredo J.;Sarma, Kavitha;Lee, Jeannie T.
通讯作者：
Lee, Jeannie T.
影响因子：
4.9
作者：
Ladner, SK;Otto, MJ;King, RW
通讯作者：
King, RW
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
25.7
作者：
Lucifora, Julie;Arzberger, Silke;Protzer, Ulrike
通讯作者：
Protzer, Ulrike
DOI：
10.1016/j.bpg.2014.07.017
发表时间：
2014-10-01
影响因子：
3.2
作者：
Colombo, Massimo;Iavarone, Massimo
通讯作者：
Iavarone, Massimo