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.

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 vFLIP-induced 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.

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