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 CA104397