Hexachlorophene suppresses β-catenin expression by up-regulation of Siah-1 in EBV-infected B lymphoma cells

Many studies have shown that the activation of β-catenin signaling can promote oncogenesis, and it is therefore of interest to find agents that modulate this pathway. Recent work has shown using B lymphoma cells that infection by Epstein-Barr virus (EBV) and expression of its latent membrane protein (LMP)-1, cause increases in the expression of β-catenin and cellular transformation. Conversely, results from cell-based small molecule screening studies have shown that the antibiotic hexachlorophene can down-regulate β-catenin in colon cancer cells. Here we report that hexachlorophene also counteracts the elevated β-catenin levels in EBV-infected B lymphomas. This is associated with restoration in levels of Siah-1 (an E3 ubiquitin ligase that is active in β-catenin regulation) which had been diminished by LMP-1. Our results suggest that Siah-1 is targeted by both LMP-1 and hexachlorophene with opposite effects. The hexachlorophene modulation of Siah-1 and β-catenin is independent of p53 and results in reduced expression of cyclin-D1 and c-Myc (target genes of β-catenin), leading to the growth arrest of B lymphoma cells. From these results we propose that hexachlorophene may provide a novel therapeutic strategy for EBV-infected B lymphoma cells by reducing β-catenin levels via the restoration of Siah-1.