A20 is a negative regulator of the NF-kappaB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappaB in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappaB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappaB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappaB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappaB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.

Concurrent chemoradiotherapy using multidrug resistance-nonrelated agents and etoposide is a safe and effective treatment for localized nasal NK/T-cell lymphoma and warrants further investigation.

Intestinal cancer is one of the most common human cancers. Aberrant activation of the canonical Wnt signaling cascade, for example, caused by adenomatous polyposis coli (APC) gene mutations, leads to increased stabilization and accumulation of ␤-catenin, resulting in initiation of intestinal carcinogenesis. The aryl hydrocarbon receptor (AhR) has dual roles in regulating intracellular protein levels both as a ligand-activated transcription factor and as a ligand-dependent E3 ubiquitin ligase. Here, we show that the AhR E3 ubiquitin ligase has a role in suppression of intestinal carcinogenesis by a previously undescribed ligand-dependent ␤-catenin degradation pathway that is independent of and parallel to the APC system. This function of AhR is activated by both xenobiotics and natural AhR ligands, such as indole derivatives that are converted from dietary tryptophan and glucosinolates by intestinal microbes, and suppresses intestinal tumor development in Apc Min/؉ mice. These findings suggest that chemoprevention with naturally-occurring and chemically-designed AhR ligands can be used to successfully prevent intestinal cancers.cecal cancer ͉ ubiquitin ligase ͉ ␤-catenin ͉ tumor chemoprevention

CHIP is a U-box-type ubiquitin ligase that induces ubiquitylation and degradation of its substrates, which include several oncogenic proteins. The relationship between CHIP and tumour progression, however, has not been elucidated. Here, we show that CHIP suppresses tumour progression in human breast cancer by inhibiting oncogenic pathways. CHIP levels were negatively correlated with the malignancy of human breast tumour tissues. In a nude mouse xenograft model, tumour growth and metastasis were significantly inhibited by CHIP expression. In contrast, knockdown of CHIP (shCHIP) in breast cancer cells resulted in rapid tumour growth and metastastic phenotypes in mice. In cell-based experiments, anchorage-independent growth and invasiveness of shCHIP cells was significantly elevated due to increased expression of Bcl2, Akt1, Smad and Twist. Proteomic analysis identified the transcriptional co-activator SRC-3 (refs 13, 14, 15, 16, 17, 18, 19) as a direct target for ubiquitylation and degradation by CHIP. Knocking down SRC-3 in shCHIP cells reduced the expression of Smad and Twist, and suppressed tumour metastasis in vivo. Conversely, SRC-3 co-expression prevented CHIP-induced suppression of metastasis formation. These observations demonstrate that CHIP inhibits anchorage-independent cell growth and metastatic potential by degrading oncogenic proteins including SRC-3.