Prostate cancer is one of the most common cancers in men, yet no gene has ever been identified that is consistently mutated in this cancer type. The tide might be about to turn, though, as Goutham Narla and colleagues now report a potential tumour-suppressor gene that is deleted in 50–60% of prostate cancers.

Chromosome 10p is deleted in over half of sporadic prostate cancers, so the authors searched this region for potential tumour-suppressor genes. The krüppel-like factor family of transcription factors has been implicated in growth, development and carcinogenesis, so they were intrigued by the fact that a member of this family, KLF6, resides in this region. Microsatellite analysis of tumour versus normal tissue from 22 patients with prostate cancer revealed that 17 of them had lost a copy of KLF6. Further mutation analysis showed that 12 of them had mutations in the remaining copy of KLF6, and that these mutations were not present in normal prostate tissue from the same individuals, confirming that the mutations were somatic. In total, 18 of 33 prostate tumours analysed (55%) had KLF6 mutations.

If KLF6 is a tumour suppressor, what is its normal function and how does its inactivation lead to cancer? In an inducible expression system, upregulation of KLF6 expression reduced cell proliferation and caused a fivefold increase in levels of the cyclin-dependent kinase inhibitor WAF1 (also known as p21), in a p53-independent manner. A luciferase reporter assay revealed that WAF1 is a direct target of KLF6, and deletion analysis pinpointed the KLF6-binding region to two GC boxes in the WAF1 promoter. By contrast, constructs encoding four of the different mutant forms of KLF6 found in prostate cancer samples were incapable of upregulating WAF1 expression.

But KLF6 — now the top-scoring tumour suppressor in prostate cancer — is ubiquitously expressed; is its loss uniquely important in the aetiology of prostate cancer, or might it also be involved in the initation of other tumour types?