Breaking Advances Highlights from Recent Cancer Literature
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چکیده
Polycomb proteins represent epigenetic regulators and exert transcriptional repression via polycomb repressive complexes (PRC). EZH2 is a component of PRC2, where it functions as a lysine methyl transferase, particularly for histones. In cancer, EZH2 is found to be overexpressed, and in glioblastoma multiforme, EZH2 has been shown to be important for maintenance of glioma stem cells (GSC). Although EZH2 is best understood as a histone methyltransferase, it has recently been shown to interact with other transcription factors via direct methylation. Accordingly, Kim and colleagues investigated possible partners of EZH2 in glioblastoma. Coimmunoprecipitation experiments showed an interactionwith STAT3. This interactionwas lost uponwithdrawal of growth factors in the medium of cultured glioma cells. Importantly, shRNA depletion of EZH2 resulted in loss of STAT3 activation, as measured by loss of phosphorylation. This finding was confirmed with pharmacologic EZH2 inhibitors. EZH2 was shown to methylate STAT3, and STAT3 methylation by EZH2 at lysine residue 180 was correlated with STAT3 activation. Sitedirected mutagenesis of lysine 180 resulted in loss of neurosphere formation by GSCs. The authors then examined upstream events and showed that AKT activity was required for the EZH2– STAT3 interaction, which was mediated by phosphorylation at serine 21 of EZH2. Mutation of serine 21 to alanine resulted in loss of neurosphere formation, loss of STAT3methylation and loss of tumor aggressiveness in SCID mice. Expression of serine 21 phosphorylated-EZH2 in patient samples was correlated with poor outcome. These findings identify a new role for EZH2, in addition to its role in transcriptional silencing, with a direct link to STAT3 activation via methylation and identify an AKT–EZH2–STAT3 axis as a positive regulator of GSC selfrenewal. These findings also suggest EZH2 as a possible therapeutic target in glioblastoma.
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تاریخ انتشار 2013