A20: from ubiquitin editing to tumour suppression

Key Points Protracted activation of the immune system by persistent inflammation or chronic infection can be oncogenic. Nuclear factor-κB (NF-κB) transcription factors are normally activated in a transient manner in response to inflammation, infection and other cellular stresses to provide pro-inflammatory and pro-survival signals to regain homeostasis. Failure to downregulate persistent NF-κB signalling can instead facilitate the manifestation of all six hallmarks of cancer: self-sufficient cell growth, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. Ubiquitylation is a post-translational modification that tightly regulates the activity of signalling proteins in NF-κB transduction cascades. A20 is a central regulator of inflammation and functions as a ubiquitin-editing enzyme to potently downregulate NF-κB signalling. A20 is inactivated in various haematological malignancies and results in constitutive NF-κB activation in tumour cells; therefore, A20 is a crucial tumour suppressor. The identification of A20 as a tumour suppressor establishes new links between ubiquitylation, NF-κB activation and tumorigenesis that may be exploited in the clinic for improved patient care. Recent reports have identified the ubiquitin-editing enzyme A20 as a crucial tumour suppressor in various lymphomas. This Review analyses how deregulation of ubiquitylation in the NF-κB signalling pathway can promote tumorigenesis. Clinicians have suspected for hundreds of years that chronic activation of the immune system contributes to the development of cancer. However, the molecular mechanisms that mediate this precarious interplay are only now being elucidated. Recent reports have identified A20 as a crucial tumour suppressor in various lymphomas. A20 is a ubiquitin-editing enzyme that attenuates the activity of proximal signalling complexes at pro-inflammatory receptors. In this Review we summarize the evidence linking chronic inflammation with tumorigenesis and consider how A20 modulates inflammatory signalling cascades, thereby providing a mechanism to explain how deregulation of ubiquitylation can promote tumorigenesis.