Tumorigenesis

DJ-1, a novel regulator of the tumor suppressor PTEN. Kim, R. H. et al. Cancer Cell 7, 263–273 (2005)

PTEN is a tumour suppressor that inhibits the phosphatidylinositol 3-kinase (PI3K) pathway that regulates cell survival. How PTEN activity is controlled is uncertain, but now Kim et al. show that the candidate oncoprotein DJ-1 is a suppressor of PTEN. Overexpression of DJ-1 in mammalian cells blocked PTEN-induced cell death and boosted expression of PI3K downstream effectors. The authors suggest that DJ-1 might be a useful prognostic marker, as non-small-cell lung carcinomas with increased DJ-1 have a poor prognosis.

Epigenetics

Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Fraga, M. F. et al. Nature Genet. 37, 391–400 (2005)

The focus of cancer epigenetics has mainly been on aberrant DNA methylation, but Fraga et al. now highlight the importance of histone modifications. They find altered histone H4 modifications in a range of cancer cell lines and primary tumours. Examining a mouse model of multistage skin cancer showed that the changes begin early in, and progress throughout, tumorigenesis. As histone-deacetylase inhibitors are currently being developed to treat cancer, defining the histone modifications that occur during tumorigenesis will be vital.

Therapeutics

ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Gumireddy, K. et al. Cancer Cell 7, 275–286 (2005)

Patients with high levels of Polo-like kinase 1 (PLK1) are less likely to survive than those with lower levels. PLK1 helps to regulate the mitotic spindle, and Gumireddy et al. identify a small-molecule inhibitor of PLK1, ON01910, that induces mitotic arrest and apoptosis in tumour cells by competing for the substrate-binding site of the kinase. ON01910 has little toxicity, markedly slows tumour growth and can work in synergy with several current chemotherapeutic agents.

Cancer suppression

DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Barkova, J. et al. Nature 434, 864–870 (2005)

What is the nature of the anticancer barrier that constrains human cancer progression? Jiri Bartek and colleagues have found that markers of an activated DNA-damage response are commonly expressed in early precursor lesions, and are induced in vitro following the expression of oncogenes that deregulate DNA replication. Furthermore, a genome-wide assessment of tumour DNA indicates that human cells activate an ATR/ATM-regulated DNA-damage response before genomic instability and malignancy are apparent.