Kaposi’s sarcoma-associated herpesvirus (KSHV) establishes a latent infection, and viral genes are poised to be transcribed in the latent chromatin. In the poised chromatins, KSHV latency-associated nuclear antigen (LANA) interacts with cellular chromodomain-helicase-DNA-binding protein 4 (CHD4) and inhibits viral promoter activation. CHD4 is known to regulate cell differentiation by preventing enhancers from activating promoters. Here, we identified a putative CHD4 inhibitor peptide (VGN73) from the LANA sequence corresponding to the LANA-CHD4 interaction surface. The VGN73 interacts with CHD4 at its PHD domain with a dissociation constant (K_D) of 14 nM. Pre-treatment with VGN73 enhanced monocyte differentiation into macrophages and globally altered the repertoire of activated genes in U937 cells. Furthermore, the introduction of the peptide into the cancer cells induced caspase-mediated CHD4 cleavage, triggered cell death, and inhibited tumor growth in a xenograft mouse model. The VGN73 may facilitate cell differentiation therapy.

中文翻译：

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LANA 肽通过诱导 CHD4 蛋白切割来抑制肿瘤生长并触发细胞死亡


卡波西肉瘤相关疱疹病毒 （KSHV） 建立潜伏感染，病毒基因准备在潜伏染色质中转录。在稳定的染色质中，KSHV 潜伏期相关核抗原 （LANA） 与细胞染色质结构域解旋酶 DNA 结合蛋白 4 （CHD4） 相互作用并抑制病毒启动子激活。已知 CHD4 通过阻止增强子激活启动子来调节细胞分化。在这里，我们从对应于 LANA-CHD4 相互作用表面的 LANA 序列中鉴定出一种推定的 CHD4 抑制剂肽 （VGN73）。VGN73 在其 PHD 结构域与 CHD4 相互作用，解离常数 （K_D） 为 14 nM。用 VGN73 预处理增强了单核细胞向巨噬细胞的分化，并全面改变了 U937 细胞中活化基因的库。此外，在异种移植小鼠模型中，将肽引入癌细胞诱导 caspase 介导的 CHD4 切割，触发细胞死亡，并抑制肿瘤生长。VGN73 可能促进细胞分化治疗。