Gene expression profiles of H16N2 cells expressing EZH2 variants. Gene expression profiles of H16N2 cells expressing EZH2 variants

A cytosolic role for EZH2 in regulating cell signaling via interaction with the VAV family of proteins has been reported by us previously. However, it is unclear whether EZH2 interactions with VAV are critical for tumorigenesis. Here, we show that cytosolic EZH2 exhibits greater transforming/metastatic capacity than wild-type EZH2 and that targeted disruption of the EZH2-VAV interaction abolishes EZH2-promoted tumorigenesis. We also found that interaction of cytosolic EZH2 with VAV is critical for EZH2-mediated talin methylation and subsequent STAT3 activation. Both cytosolic EZH2 and a methyl-mimicking talin mutant substantially promoted STAT3 activation and tumor growth. We therefore propose that the VAV-dependent cytosolic function of EZH2 may be a critical step in the initiation of cellular transformation, preceding the well-established function of EZH2 in epigenetic silencing of tumor suppressors. Thus, disrupting EZH2-VAV interaction could be an alternative intervention strategy for treatment of cancers associated with EZH2 overexpression.