A truncated form of IKKα is responsible for specific nuclear IKK activity in colorectal cancer

Nuclear IKKα regulates gene transcription by phosphorylating specific substrates and has been linked to cancer progression and metastasis. However, the mechanistic connection between tumorigenesis and IKKα activity remains poorly understood. We have now analyzed 288 human colorectal cancer samples and found a significant association between the presence of nuclear IKK and malignancy. Importantly, the nucleus of tumor cells contains an active IKKα isoform with a predicted molecular weight of 45 kDa (p45-IKKα) that includes the kinase domain but lacks several regulatory regions. Active nuclear p45-IKKα forms a complex with nonactive IKKα and NEMO that mediates phosphorylation of SMRT and histone H3. Proteolytic cleavage of FL-IKKα into p45-IKKα is required for preventing the apoptosis of CRC cells in vitro and sustaining tumor growth in vivo. Our findings identify a potentially druggable target for treating patients with advance refractory CRC.P.M. is a recipient of a FPU fellowship (AP2009-2892) and M.C.M. is funded by the ‘‘Sara Borrell’’ Program from MICIN (CD09/00421). This work was supported by Fondo de Investigaciones Sanitarias (PI07/0778 and PI10/01128), AGAUR (2009SGR23), Fondos Feder RD06/0020/0098 and RD09/0076/00036, and Xarxa de Bancs de tumors sponsored by Pla Director d’Oncologia de/nCatalunya (XBTC). M.W.M. was supported by funds from the NIH/NCI R01 CA10439

Inhibition of specific NF-KB activity contributes to the tumor suppressor function of 14-3-3omega in breast cancer

14-3-3σ is frequently lost in human breast cancers by genetic deletion or promoter methylation. We have now investigated the involvement of 14-3-3σ in the termination of NF-κB signal in mammary cells and its putative role in cancer relapse and metastasis. Our results show that 14-3-3σ regulates nuclear export of p65-NF-κB following chronic TNFα stimulation. Restoration of 14-3-3σ in breast cancer cells reduces migration capacity and metastatic abilities in vivo. By microarray analysis, we have identified a genetic signature that responds to TNFα in a 14-3-3σ-dependent manner and significantly associates with different breast and other types of cancer. By interrogating public databases, we have found that over-expression of this signature correlates with poor relapse-free survival in breast cancer patients. Finally, screening of 96 human breast tumors showed that NF-κB activation strictly correlates with the absence of 14-3-3σ and it is significantly associated with worse prognosis in the multivariate analysis. Our findings identify a genetic signature that is important for breast cancer prognosis and for future personalized treatments based on NF-κB targeting.This work was funded by ISCIII/FEDER-Subdirección General de Evaluación y Fomento de la Investigación (PI07/0778, PI10/01128, PS09/1296 and PS09/01285), AGAUR (2009SGR23 and 2009SGR321) and Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I), iniciativa Ingenio 2010, Programa Consolider and Instituto de Salud Carlos III (ISCIII)/FEDER (RD06/0020/0098 and RD06/0020/0109). Financial support was provided to RRG by BBVA foundation and Asociación Española Contra el Cáncer. NLB acknowledges funding from the Spanish Ministry of Science and Technology (SAF2009-06954). AJ-S was funded by Science and Education Spanish Ministry (MEC) FPI predoctoral fellowship (BES-2008-001850). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip

Chromatin-bound IκB-alpha regulates a subset of polycomb target genes in differentiation and cancer

IκB proteins are the primary inhibitors of NF-κB. Here, we demonstrate that sumoylated and phosphorylated IκBα accumulates in the nucleus of keratinocytes and interacts with histones H2A and H4 at the regulatory region of HOX and IRX genes. Chromatin-bound IκBα modulates Polycomb recruitment and imparts their competence to be activated by TNF-alpha. Mutations in the Drosophila IκBα gene cactus enhance the homeotic phenotype of Polycomb mutants, which is not counteracted by mutations in dorsal/NF-κB. Oncogenic transformation of keratinocytes results in cytoplasmic IκBα translocation associated with a massive activation of Hox. Accumulation of cytoplasmic IκBα was found in squamous cell carcinoma (SCC) associated with IKK activation and HOX upregulation