Abeloff V Scholar*
Enzymes that modify chromatin (the physiological form of DNA) are often found abnormally expressed, mutated, and/or hyper-activated among various forms of blood malignancies. Somatic mutations of EZH2, a gene that encodes a critical chromatin-modulating enzyme, are responsible for over 10-20% of clinically diagnosed diffused large B-cell lymphomas and follicular lymphoma. These mutations are known to lead to EZH2 hyperactivity in cancer cells. However, it is largely unclear how EZH2 is associated with chromatin, which is critical for EZH2’s role in gene control and cancer promotion. Using the biochemical approach as a discovery tool, we demonstrate that the activities of EZH2 rely on a critical interacting factor PHF19 or PHF1, which opens a possibility for pharmacological manipulation and makes them ideal drug targets. Abnormalities of both PHF1 and PHF19 have been frequently found in human cancers including lymphoma patients, which resonate well with their roles in regulating EZH2 during cancer development. Future investigation shall be performed to design new ways for targeting EZH2’s cofactors as novel anti-cancer interventions.
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