Fig. 1: A cluster of breast cancer cells undergoing apoptosis—a last-resort ‘self-destruct’ mechanism employed by cells to prevent uncontrolled growth.
© 2010 Wellcome Collection
For several genes involved in cell division, the E2F1 protein acts as a master regulator but it can also help initiate the cellular suicide mechanism known as apoptosis (Fig. 1). Accordingly, misregulation of E2F1 activity is commonly observed in a variety of cancers, typically through disruption of Rb repressor protein function. “Ninety percent of small cell lung cancers have Rb mutations, which can cause E2F1 activation,” says Qiang Yu of the A*STAR Genome Institute of Singapore, “and many other human cancers also have [enhanced] E2F1 activity.”
Why hyperactivation of E2F1 is not accompanied by increased levels of apoptotic cell death remains poorly understood. Some researchers have suggested that this function may be suppressed by the introduction of inhibitory chemical modifications—known as ‘epigenetic’ marks—onto genes that help drive this activity, and Yu and co-workers have recently published new data supporting this model.
The researchers began by looking at EZH2, a major regulatory target of E2F1 and an enzyme that facilitates the epigenetic inhibition of a number of tumor suppressor genes. Initial experiments revealed that the gene encoding the pro-apoptotic Bim protein is activated by E2F1, but the resultant enhanced expression is normally kept in check by the repressive action of EZH2. They subsequently demonstrated that EZH2 binds directly to regulatory elements on the BIM gene in an E2F1-dependent manner.
Cancer cells with artificially reduced EZH2 expression, however, generally entered growth arrest rather than undergoing apoptosis. Yu and his co-workers therefore hypothesized that a parallel cellular signaling pathway was preventing the onset of cell death. Enzymes known as kinases are a standard component of such pathways, and the researchers performed a screen with a library of kinase inhibitors to identify compounds that might facilitate apoptosis. Two candidates emerged from this screen, each of which appears to work by reducing expression of the anti-apoptotic factor MCL-1. Importantly, however, these kinase inhibitors exclusively triggered cell death in cells in which EZH2 levels had been markedly reduced.
These findings confirm an important role for this epigenetic regulator in preventing E2F1-mediated cell death. “We provide the first evidence that EZH2 can directly inhibit apoptotic genes in certain contexts,” says Yu. “This mechanism may contribute to the oncogenic function of EZH2 in human cancer.” As such, EZH2 activity may represent an important ‘fail-safe’ system that enables tumor cells to thrive in spite of E2F1 overexpression, and could potentially offer a useful target for future therapeutic strategies.
The A*STAR-affiliated researchers mentioned in this highlight are from the Genome Institute of Singapore.
