β-catenin: A crucial transcriptional activator of KSHV latency genes and small molecule target in primary effusion lymphoma.

Latency-associated nuclear antigen (LANA)-induced β-catenin accumulation is one of the prime events in the Kaposi sarcoma-associated herpesvirus (KSHV)-associated primary effusion lymphoma (PEL). LANA interacts with GSK3β, which in turn increases β-catenin pool in this lymphoma. The intrinsic molecular mechanism and the effects of β-catenin accumulation in this lymphoma is still unclear. β-catenin acts as a major transcription factor that regulates a variety of proliferative signaling pathways and promotes oncogenesis. Here, we report that the accumulated β-catenin in this lymphoma is active and mediates transcriptional modulation of the KSHV latency genes. The modulated latency genes exert positive effects on other proliferative pathways. Interestingly, β-catenin directly binds to latency promoter at different affinities to modulate the promoter activity. This, in turn, activates the transcription of latency genes and the other known target genes of β-catenin. Hence, these results suggest that β-catenin signaling pathway may serve as a potential target against this lymphoma. The downregulation of β-catenin protein level or its activity would be one of the most promising approaches for lymphoma treatment. The small-molecule-based inhibition of β-catenin markedly inhibits the transcription of latency genes and promotes apoptosis. Hence, a new mechanism of oncogenesis in PEL is ascribed to β-catenin. Moreover, the evaluation of other small-molecule inhibitors of β-catenin will open a path to combat lymphoma in the future.