Repression of Hox genes by LMP1 in nasopharyngeal carcinoma and modulation of glycolytic pathway genes by HoxC8.
Repression of Hox genes by LMP1 in nasopharyngeal carcinoma and modulation of glycolytic pathway genes by HoxC8.
复制标题
鼻咽癌中LMP1对Hox基因的抑制以及HoxC8对糖酵解途径基因的调节
作者：
Jiang Y;Yan B;Lai W;Shi Y;Xiao D;Jia J;Liu S;Li H;Lu J;Li Z;Chen L;Chen X;Sun L;Muegge K;Cao Y;Tao Y
EB病毒（Epstein-Barr virus，EBV）引起人类淋巴系统恶性肿瘤，并且EBV产物潜伏膜蛋白1（LMP 1）已被鉴定为上皮癌如鼻咽癌（NPC）中的癌基因。EB病毒可以表观遗传重编程淋巴细胞特异性过程并诱导细胞永生化。然而，LMP 1和NPC宿主细胞之间的相互作用在很大程度上仍然未知。在这里，我们报告说，LMP 1是重要的，以建立在NPC细胞系和肿瘤活检的Hox基因表达签名。LMP 1通过RNA聚合酶II（RNA Pol II）的停滞诱导几个Hox基因的阻遏。Pol II停滞可以通过涉及表观遗传调节剂TET 3的照射来克服。此外，我们报告说，HoxC 8，LMP 1沉默的基因之一，在肿瘤生长中发挥作用。HoxC 8的异位表达在体内外抑制鼻咽癌细胞生长，调节糖酵解和调节三羧酸（TCA）循环相关基因的表达。我们认为病毒潜伏产物可能通过阻止关键介质进而调节糖酵解来抑制。
Epstein-Barr virus (EBV) causes human lymphoid malignancies, and the EBV product latent membrane protein 1 (LMP1) has been identified as an oncogene in epithelial carcinomas such as nasopharyngeal carcinoma (NPC). EBV can epigenetically reprogram lymphocyte-specific processes and induce cell immortalization. However, the interplay between LMP1 and the NPC host cell remains largely unknown. Here, we report that LMP1 is important to establish the Hox gene expression signature in NPC cell lines and tumor biopsies. LMP1 induces repression of several Hox genes in part via stalling of RNA polymerase II (RNA Pol II). Pol II stalling can be overcome by irradiation involving the epigenetic regulator TET3. Furthermore, we report that HoxC8, one of the genes silenced by LMP1, has a role in tumor growth. Ectopic expression of HoxC8 inhibits NPC cell growth in vitro and in vivo, modulates glycolysis and regulates the expression of tricarboxylic acid (TCA) cycle-related genes. We propose that viral latency products may repress via stalling key mediators that in turn modulate glycolysis.