Suppression of the SAP18/HDAC1 complex by targeting TRIM56 and Nanog is essential for oncogenic viral FLICE-inhibitory protein-induced acetylation of p65/ReIA, NF-κB activation, and promotion of cell invasion and angiogenesis
Suppression of the SAP18/HDAC1 complex by targeting TRIM56 and Nanog is essential for oncogenic viral FLICE-inhibitory protein-induced acetylation of p65/ReIA, NF-κB activation, and promotion of cell invasion and angiogenesis
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通过靶向 TRIM56 和 Nanog 抑制 SAP18/HDAC1 复合物对于致癌病毒 FLICE 抑制蛋白诱导的 p65/ReIA 乙酰化、NF-κ B 激活以及促进细胞侵袭和血管生成至关重要
DOI：
10.1038/s41418-018-0268-3
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发表时间：
2019-10-01
影响因子：
12.4
通讯作者：
Lu, Chun
中科院分区：
文献类型：
--
作者：
Ding, Xiangya;Xu, Jingyun;Lu, Chun
卡波西肉瘤 (KS) 是一种高度侵袭性和血管生成的内皮梭形细胞肿瘤，是由 KS 相关疱疹病毒 (KSHV) 感染引起的最常见的艾滋病相关癌症。 KSHV 编码的病毒 FLICE 抑制蛋白 (vFLIP) 是一种病毒致癌蛋白，但其在 KSHV 诱导的癌症传播和血管生成中的作用仍不清楚。在这里，我们报告 vFLIP 通过下调 SAP18-HDAC1 复合物来促进细胞迁移、侵袭和血管生成。 vFLIP 通过招募 E3 泛素连接酶 TRIM56，通过泛素-蛋白酶体途径降解 SAP18。此外，vFLIP 通过抑制 Nanog 在 HDAC1 启动子上的占据来抑制 HDAC1（SAP18 的蛋白质伴侣）。值得注意的是，vFLIP 损害 SAP18/HDAC1 复合物和 p65 亚基之间的相互作用，导致 p65 乙酰化和 NF-kappa B 激活增强。我们的数据表明 vFLIP 激活 NF-kappa B 的新机制是通过减少 SAP18/HDAC1 复合物促进 p65 亚基的乙酰化，这有助于 vFLIP 诱导 NF-kappa B 通路的激活、细胞侵袭和血管生成。这些发现增进了我们对 KSHV 诱导发病机制的理解，并为以 vFLIP/SAP18/HDAC1 复合物为靶点的治疗作为 AIDS-KS 的新策略提供了理论基础。
Kaposi's sarcoma (KS), a highly invasive and angiogenic tumor of endothelial spindle-shaped cells, is the most common AIDS-associated cancer caused by KS-associated herpesvirus (KSHV) infection. KSHV-encoded viral FLICE-inhibitory protein (vFLIP) is a viral oncogenic protein, but its role in the dissemination and angiogenesis of KSHV-induced cancers remains unknown. Here, we report that vFLIP facilitates cell migration, invasion, and angiogenesis by downregulating the SAP18-HDAC1 complex. vFLIP degrades SAP18 through a ubiquitin-proteasome pathway by recruiting E3 ubiquitin ligase TRIM56. Further, vFLIP represses HDAC1, a protein partner of SAP18, by inhibiting Nanog occupancy on the HDAC1 promoter. Notably, vFLIP impairs the interaction between the SAP18/HDAC1 complex and p65 subunit, leading to enhancement of p65 acetylation and NF-kappa B activation. Our data suggest a novel mechanism of vFLIP activation of the NF-kappa B by decreasing the SAP18/HDAC1 complex to promote the acetylation of p65 subunit, which contributes to vFLIP-induced activation of the NF-kappa B pathway, cell invasion, and angiogenesis. These findings advance our understanding of the mechanism of KSHV-induced pathogenesis, and providing a rationale for therapeutic targeting of the vFLIP/SAP18/HDAC1 complex as a novel strategy of AIDS-KS.