Viral interleukin-6 encoded by an oncogenic virus promotes angiogenesis and cellular transformation by enhancing STAT3-mediated epigenetic silencing of caveolin 1.
Viral interleukin-6 encoded by an oncogenic virus promotes angiogenesis and cellular transformation by enhancing STAT3-mediated epigenetic silencing of caveolin 1.
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由致癌病毒编码的病毒白细胞介素 6 通过增强 STAT3 介导的 Caveolin 1 表观遗传沉默来促进血管生成和细胞转化
DOI：
10.1038/s41388-020-1317-1
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发表时间：
2020-06
期刊：
影响因子：
8
通讯作者：
Lu C
中科院分区：
文献类型：
--
作者：
Li W;Wang Q;Qi X;Guo Y;Lu H;Chen Y;Lu Z;Yan Q;Zhu X;Jung JU;Tosato G;Gao SJ;Lu C
卡波西肉瘤（KS）由致癌性卡波西肉瘤相关疱疹病毒（KSHV）引起，是一种高度血管生成和侵袭性血管肿瘤，是最常见的艾滋病相关癌症。kshv编码的病毒白细胞介素-6 （vIL-6）与kshv诱导的恶性肿瘤的发展有关；然而，il -6诱导血管生成和肿瘤发生的机制仍不清楚。在这里，我们发现vIL-6通过下调CAV1 （CAV1）促进血管生成、细胞增殖和侵袭，CAV1在多种癌症相关过程中起着关键和广泛的作用。从机制上讲，vIL-6信号传导导致靶向DNA甲基转移酶1 （DNMT1）的STAT3依次磷酸化和乙酰化。具体来说，vil -6诱导的STAT3磷酸化形式转录激活了DNMT1的表达。此外，vil -6诱导的乙酰化形式的STAT3与DNMT1相互作用，形成一个转录因子复合物，结合并甲基化CAV1启动子，导致CAV1表达沉默。事实上，下调CAV1表达可激活AKT信号，促进KSHV诱导的细胞侵袭和生长转化。最后，KSHV基因组中vIL-6的基因缺失消除了KSHV诱导的细胞转化和受损的血管生成。我们的研究结果表明，vIL-6通过调控STAT3-DNMT1复合物的形成，从表观遗传学上沉默CAV1的表达，从而促进血管生成和肿瘤发生。这些新发现明确了KSHV抑制CAV1通路的机制，并为靶向该通路治疗KSHV相关癌症奠定了科学基础。
Kaposi’s sarcoma (KS) caused by oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) is a highly angiogenic and invasive vascular tumor and the most common AIDS-associated cancer. KSHV-encoded viral interleukin-6 (vIL-6) is implicated in the development of KSHV-induced malignancies; however, the mechanisms underlying vIL-6-induced angiogenesis and tumorigenesis remain undefined. Here, we show that vIL-6 promotes angiogenesis, cell proliferation, and invasion by downregulating caveolin 1 (CAV1) that plays a pivotal and versatile role in multiple cancer-associated processes. Mechanistically, vIL-6 signaling led to the phosphorylation and acetylation of STAT3 that targeted DNA methyltransferase 1 (DNMT1) in a sequential manner. Specifically, the vIL-6-induced phosphorylated form of STAT3 transcriptionally activated DNMT1 expression. Furthermore, vIL-6-induced acetylated form of STAT3 interacted with DNMT1 to form a transcription factor complex that bound to and methylated the CAV1 promoter, leading to CAV1 expression silencing. In fact, downregulation of CAV1 expression resulted in the activation of AKT signaling, promoting cell invasion, and growth transformation induced by KSHV. Finally, genetic deletion of vIL-6 from the KSHV genome abolished KSHV-induced cellular transformation and impaired angiogenesis. Our results reveal that vIL-6 epigenetically silences CAV1 expression to promote angiogenesis and tumorigenesis by regulating the formation of STAT3-DNMT1 complex. These novel findings define a mechanism by which KSHV inhibits the CAV1 pathway and establish the scientific basis for targeting this pathway to treat KSHV-associated cancers.
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影响因子：
6.4
作者：
Lee MS;Yuan H;Jeon H;Zhu Y;Yoo S;Shi S;Krueger B;Renne R;Lu C;Jung JU;Gao SJ
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