EZH2: Cancer Villain or MDS Hero?

EZH2 takes a lot of abuse, and is often labeled as a dreaded oncogene , but like a movie villain who redeems themselves in the end, the histone methyltransferase isn’t all evil. According to two new papers published simultaneously in Nature Genetics, EZH2 may in fact function as a tumor suppressor in some blood cancers.

EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), which methylates lysine 27 of histone H3 to epigenetically silence genes involved in cell fate decisions. EZH2 overexpression has been frequently seen in epithelial tumors. Interestingly, it has also been associated with a miRNA, (miR-101) that has been shown to repress EZH2 and, presumably, protect against prostate and bladder cancers.

-3jpg

However, when Joop Jansen at Radboud University Nijmegen Medical Centre and coworkers in the Netherlands and Belgium examined aberrant chromosomal regions of patients with myelodysplastic syndromes (MDS), they tagged EZH2 as a gene frequently deleted or mutated. They also showed that MDS patients with EZH2 deletions or point mutations showed significantly worse survival rates compared to patients with normal EZH2 genes.

In a related paper, Nicholas Cross at the University of Southampton, UK, and colleagues in Europe likewise linked inactivating EZH2 mutations with myeloid disorders and poor prognosis. Moreover, they showed that missense mutations in the evolutionarily conserved SET domain of EZH2 correlated with absent or reduced EZH2 catalytic activity.

These results suggest that EZH2 acts as an oncogene in certain cellular contexts and as a tumor suppressor in others. Therefore, attempts to globally dampen EZH2 activity to treat some cancers may be unwise because they could actually promote other myeloid problems. Be a Lab Hero and find out more at Nature Genetics, Jansen et al. July 2010 and Nature Genetics, Cross et al July 2010.