Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB

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Abstract
Protein modification by the conjugation of ubiquitin moieties—ubiquitination—plays a major part in many biological processes, including cell cycle and apoptosis1. The enzymes that mediate ubiquitin-conjugation have been well-studied, but much less is known about the ubiquitin-specific proteases that mediate de-ubiquitination of cellular substrates2,3. To study this gene family, we designed a collection of RNA interference vectors to suppress 50 human de-ubiquitinating enzymes, and used these vectors to identify de-ubiquitinating enzymes in cancer-relevant pathways. We report here that inhibition of one of these enzymes, the familial cylindromatosis tumour suppressor gene (CYLD)4, having no known function, enhances activation of the transcription factor NF-κB. We show that CYLD binds to the NEMO (also known as IKKγ) component of the IκB kinase (IKK) complex, and appears to regulate its activity through de-ubiquitination of TRAF2, as TRAF2 ubiquitination can be modulated by CYLD. Inhibition of CYLD increases resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis. We show that this effect can be relieved by aspirin derivatives that inhibit NF-κB activity5, which suggests a therapeutic intervention strategy to restore growth control in patients suffering from familial cylindromatosis.