Viral interleukin-6 encoded by an oncogenic virus promotes angiogenesis and cellular transformation by enhancing STAT3-mediated epigenetic silencing of caveolin 1.

Abstract

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.

• Authors: Wan Li, Qingxia Wang, Xiaoyu Qi, Yuanyuan Guo, Hongmei Lu, Yuheng Chen, Zhongmou Lu, Qin Yan, Xiaofei Zhu, Jae U Jung, Giovanna Tosato, Shou-Jiang Gao, Chun Lu
• Journal: Oncogene (Oncogene) Vol. 39 Issue 23 Pg. 4603-4618 (06 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 32393833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CAV1 protein, human
• Caveolin 1
• Interleukin-6
• STAT3 Transcription Factor
• STAT3 protein, human
• DNA (Cytosine-5-)-Methyltransferase 1
• DNMT1 protein, human

Topics

• Acetylation
• Caveolin 1 (genetics)
• Cell Proliferation (genetics)
• Cell Transformation, Neoplastic (genetics)
• DNA (Cytosine-5-)-Methyltransferase 1 (metabolism)
• Down-Regulation (genetics)
• Herpesvirus 8, Human (genetics, metabolism)
• Humans
• Interleukin-6 (genetics, metabolism)
• Neoplasm Invasiveness (genetics)
• Neovascularization, Pathologic (genetics)
• Phosphorylation (genetics)
• Promoter Regions, Genetic (genetics)
• STAT3 Transcription Factor (genetics, metabolism)
• Sarcoma, Kaposi (genetics, pathology)
• Signal Transduction