NFκB‐dependent Bcl3 regulates survival in cutaneous T‐cell lymphoma (762.1)

Abstract

Cutaneous T cell lymphoma (CTCL) is characterized by high constitutive activity of NFκB, which promotes cell survival and resistance to apoptosis. Increased expression of the proto‐oncogene Bcl3 belonging to IκB family is associated with the pathogenesis of different types of human cancer, yet, the regulation and function of Bcl3 in CTCL have not been previously studied. Here, we show that human CTCL Hut‐78 and HH cells express high protein levels of Bcl3, which is localized both in the cytoplasm and in the nucleus. NFκB subunits p65 and p50 are highly recruited to the Bcl3 promoter, indicating that Bcl3 expression is regulated by NFκB p65/p50 heterodimers in CTCL cells. Proteasome inhibition by bortezomib (BZ), which induces apoptosis in CTCL cells, inhibits Bcl3 expression. The BZ‐decreased Bcl3 expression is associated with decreased recruitment of NFκB p65 and p50 subunits to the endogenous Bcl3 promoter, but with increased recruitment of NFκB p52. Importantly, suppression of Bcl3 levels by siRNA induces apoptosis and down‐regulates expression of the anti‐apoptotic genes cIAP1 and cIAP2 in CTCL cells. Bcl3 is specifically recruited to the endogenous cIAP1 and cIAP2 promoters, and BZ inhibits this recruitment. These data provide first insights into the regulation and function of Bcl3 in CTCL, and indicate that Bcl3 has an important pro‐survival role in these cells.Grant Funding Source: Support by NIH grants AI085497 and CA173452 to I.V.