PRC2 (polycomb repressive complex 2) has been shown to promote oncogenesis in many tumor types; however, loss of function mutations in PRC2 components has also been shown to occur in some hematopoietic malignancies, raising questions about the precise role of the complex in cancer.
In a study reported in Nature, De Raedt and colleagues showed that the polycomb group gene SUZ12 functions as a tumor suppressor in peripheral nervous system tumors, high-grade glioma, and melanoma by cooperating with mutations in NF1. Loss of NF1, which encodes a RAS GTPase-activating protein, drives tumorigenesis by activating RAS. Loss of SUZ12 was shown to potentiate the effects of NF1 mutations by amplifying RAS-driven transcription through effects on chromatin. However, inactivation of SUZ12 was also associated with an epigenetic switch that resulted in sensitivity of these cancers to bromodomain inhibitors.
The investigators concluded: “Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and RAS, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.” ■
De Raedt T, et al: Nature 514:247-251, 2014.