Bcl3 regulates pro-survival and pro-inflammatory gene expression in cutaneous T-cell lymphoma

The advanced stages of cutaneous T cell lymphoma (CTCL) are characterized not only by decreased levels of pro-inflammatory cytokines, resulting in high susceptibility to infections, but also by high constitutive activity of NFκB, which promotes cell survival and resistance to apoptosis. The increased expression of the proto-oncogene Bcl3 belonging to IκB family is associated with the pathogenesis of the different types of human cancer, yet, the function and regulation of Bcl3 in CTCL have not been studied. Here, we show that Bcl3 is highly expressed in CTCL Hut-78 and HH cells. The suppression of Bcl3 levels decreases the expression of the pro-survival genes cIAP1 and cIAP2, reduces cell viability, and increases CTCL apoptosis. Interestingly, Bcl3 suppression concomitantly increases expression and the release of the pro-inflammatory cytokines IL-8 and IL-17 in CTCL cells. Chromatin immunoprecipitation studies show that Bcl3 regulates cIAP1, cIAP2, IL-8 and IL-17 gene expression through direct binding to their promoters. Bcl3 expression is regulated by bortezomib (BZ)-mediated proteasome inhibition, and BZ inhibits Bcl3 recruitment to its target promoters, resulting in decreased expression of cIAP1 and cIAP2, but increased expression of IL-8 and IL-17. The Bcl3 expression is regulated through NFκB subunit exchange on Bcl3 promoter. In untreated cells, the Bcl3 promoter is occupied predominantly by p65/p50 heterodimers, inducing Bcl3 expression; however, in BZ-treated cells, the p65/50 heterodimers are replaced by p52 subunits, resulting in Bcl3 transcriptional repression. These data provide the first insights into the function and regulation of Bcl3 in CTCL, and indicate that Bcl3 has an important pro-survival and immunosuppressive role in these cells.