Suppression of the SAP18/HDAC1 complex by targeting TRIM56 and Nanog is essential for oncogenic viral FLICE-inhibitory protein-induced acetylation of p65/RelA, NF-κB activation, and promotion of cell invasion and angiogenesis

Abstract

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-κB activation. Our data suggest a novel mechanism of vFLIP activation of the NF-κB by decreasing the SAP18/HDAC1 complex to promote the acetylation of p65 subunit, which contributes to vFLIPinduced activation of the NF-κB 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.

Sperm associated antigen 9 promotes oncogenic KSHV-encoded interferon regulatory factor-induced cellular transformation and angiogenesis by activating the JNK/VEGFA pathway

“…EZ-Magna ChIP A/G Chromatin Immunoprecipitation Kit (Merck, Darmstadt, Germany) was used for ChIP analysis as previously described [76]. Cells (10 7 ) cross-linked by 1% formaldehyde were harvested to suffer sonication.…”

Viruses harness YxxØ motif to interact with host AP2M1 for replication: A vulnerable broad-spectrum antiviral target

“…The photomultiplier tube voltage was set as 300 to 350 V and the resolution as 50 μm. Target bands were excised and subjected to LC-electrospray ionization MS/MS analysis by Q Exactive as previously established (Shanghai Applied Protein Technology Co. Ltd.) ( 33 ). Samples with or without ACA were also incubated with DyLight 488–Phosphine to act as controls.…”

Modulation of Angiogenic Processes by the Human Gammaherpesviruses, Epstein–Barr Virus and Kaposi’s Sarcoma-Associated Herpesvirus

“…Importantly, vFLIP can directly interact with IκB kinase (IKK) α, IKKβ, and IKKγ/ NF-κB essential modulator (NEMO) complexes, promoting IκBα destruction and thus NF-κB activation (Field et al, 2003; Guasparri et al, 2004). Additionally, it was recently demonstrated that vFLIP uses an alternative pathway to induce the activation of NF-κB by promoting the degradation of the histone deacetylase complex components SAP-18 and histone deacetylase (HDAC) 1, which target p65 for deacetylation (Ding et al, 2019). Importantly, activation of NF-κB is essential for vFLIP-induced endothelial cell migration, invasion, and angiogenesis (Ding et al, 2019).…”

“…Additionally, it was recently demonstrated that vFLIP uses an alternative pathway to induce the activation of NF-κB by promoting the degradation of the histone deacetylase complex components SAP-18 and histone deacetylase (HDAC) 1, which target p65 for deacetylation (Ding et al, 2019). Importantly, activation of NF-κB is essential for vFLIP-induced endothelial cell migration, invasion, and angiogenesis (Ding et al, 2019). In an NF-κB-dependent manner, and in coordination with LANA, vFLIP increases expression of the epigenetic modifier EZH2, which in turn modulates the pro-angiogenic factor Ephrin-B2 (He et al, 2012).…”