Downregulation of ATOH8 induced by EBV-encoded LMP1 contributes to the malignant phenotype of nasopharyngeal carcinoma.
Downregulation of ATOH8 induced by EBV-encoded LMP1 contributes to the malignant phenotype of nasopharyngeal carcinoma.
复制标题
EBV编码的LMP1诱导的ATOH8下调导致鼻咽癌恶性表型
DOI：
10.18632/oncotarget.8503
复制
发表时间：
2016-05-03
期刊：
影响因子：
--
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Wang Z;Xie J;Yan M;Wang J;Wang X;Zhang J;Zhang Y;Li P;Lei X;Huang Q;Lin S;Guo X;Liu Q
鼻咽癌（NPC）恶性表型的机制仍然知之甚少。EB病毒（EBV）一致地出现在几乎所有的恶性NPC患者样本中，这表明恶性表型和EBV感染之间有很强的病因学联系。我们发现EB病毒编码的潜伏膜蛋白（LMP 1）能促进鼻咽癌细胞的生长、运动、侵袭和异种移植瘤的生长。对LMP 1阳性NPC患者组织的RNA-seq分析表明，广泛的基因抑制有助于NPC的恶性表型。转录因子结合位点（TFBS）富集分析表明包括ATOH 8的转录因子子集，ATOH 8是一种新的转录因子，其属于碱性螺旋-环-螺旋（bHLH）基因家族，反向富集上调基因和下调基因的启动子。重要的是，ATOH 8的表达在永生化正常鼻咽上皮细胞（NPEC）和LMP 1过表达的NPC细胞中均受到抑制。Real-Time PCR和Western Blot分析表明ATOH 8降低了NPC细胞系和患者样品中的表达。此外，通过功能获得或丧失测定，我们证明ATOH 8抑制促进NPC的恶性表型，而ATOH 8恢复逆转NPC的恶性表型。最后，我们证明了LMP 1通过表观遗传学上损害ATOH 8启动子上的激活性H3 K4 me 3的占据和增强抑制性H3 K27 me 3的占据来抑制ATOH 8表达。总的来说，我们的研究揭示了EB病毒感染诱导的NPC恶性表型的发生，并将新的bHLH转录因子ATOH 8作为LMP 1的新下游靶点。
Mechanism for the malignant phenotype of nasopharyngeal carcinoma (NPC) remains poorly understood. Epstein-Barr virus (EBV) consistently appears in nearly all malignant NPC patient samples, suggesting the strong etiological link between the malignant phenotype and EBV infection. Here we found that the EBV-encoded latent membrane protein (LMP1) enhanced cell growth, motility, invasion and xenograft tumor growth of NPC. RNA-seq profiling analysis of LMP1-positive NPC patient tissues indicated that widespread gene repression contributed to malignant phenotype of NPC. The transcription factor binding site (TFBS) enrichment analysis indicated a subset of transcription factors including ATOH8, a novel transcript factor which belongs to the basic helix-loop-helix (bHLH) gene family inversely enriched in promoters of up-regulated genes and down-regulated genes. Importantly, the expression of ATOH8 was suppressed in both immortalized normal nasopharyngeal epithelial cells (NPEC) and NPC cells with LMP1 overexpression. The Real-Time PCR and Western Blot assays indicated that ATOH8 decreased expression in NPC cell lines and patient samples. Moreover, by gain- or loss-of-function assays, we demonstrated that ATOH8 inhibition promoted malignant phenotype, whereas ATOH8 restoration reversed malignant phenotype of NPC. Finally, we demonstrated that LMP1 inhibited ATOH8 expression by epigenetically impairing the occupancy of activating H3K4me3 and enhancing the occupancy of repressive H3K27me3 on ATOH8 promoter. Collectively, our study uncovered the occurrence of malignant phenotype of NPC induced by EBV infection and characterized a novel bHLH transcription factor ATOH8 as a new downstream target of LMP1.
登录
查看更多内容
影响因子：
4.8
作者：
Chakrabarti, SK;James, JC;Mirmira, RG
通讯作者：
Mirmira, RG
影响因子：
4.8
作者：
Rawnsley, David R.;Xiao, Jiping;Kahn, Mark L.
通讯作者：
Kahn, Mark L.
影响因子：
4
作者：
Fang, Fang;Wasserman, Scott M.;Pei, Xuetao
通讯作者：
Pei, Xuetao
影响因子：
4.8
作者：
Rhodes, DR;Yu, JJ;Chinnaiyan, AM
通讯作者：
Chinnaiyan, AM
影响因子：
64.5
作者：
Christensen, Jesper;Agger, Karl;Helin, Kristian
通讯作者：
Helin, Kristian