Abstract A28: Targeting PCL3/PHF19 as an alternative therapeutic strategy to EZH2 inhibition in PRC2-deregulated cancers

Abstract

The Polycomb Repressive Complex 2 (PRC2) is emerging as an attractive therapeutic target for the treatment of cancer. Several functional protein domains that are amenable to small-molecule inhibition exist within the complex and the recent development of chemical inhibitors of the EZH1/2 SET domain now offers a means to therapeutically target the complex. Here we explore the potential of targeting the sub-stoichiometric PRC2 component, PCL3/PHF19, as an alternative to EZH1/2 inhibition. We show, both in normal fibroblasts and in SNF5 deficient malignant rhabdoid sarcoma cells, that targeted depletion of PCL3/PHF19 leads to proliferative defects, owing, at least in part, to a loss of Polycomb binding at and de-repression of the tumour suppressor p16INK4A. Significantly, we show that ectopic expression of PCL3/PHF19 leads to p16INK4A repression and a bypass of cellular senescence. This correlates with increased recruitment of EZH2, accumulation of H3K27me3 and PRC1 components on the INK4A promoter, suggesting a potential oncogenic role for PCL3/PHF19. Consistent with this, PCL3/PHF19 is over-expressed in many cancers. Previously we demonstrated that the TUDOR domain of PCL3/PHF19 is required for the ability of the protein to read epigenetic modifications and facilitate the recruitment of EZH2 to chromatin. Taken together with the data presented here, we propose that the TUDOR domain of PCL3/PHF19 represents a viable alternative functional domain within the PRC2 complex for small-molecule inhibition. Citation Format: Gerard L. Brien, Emilia Jerman, Matthew Campbell, Bracken P. Adrian. Targeting PCL3/PHF19 as an alternative therapeutic strategy to EZH2 inhibition in PRC2-deregulated cancers. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A28.

Peritoneal Modulators of EZH2-miR-155 Cross-Talk in Endometriosis

“…In addition to the known binding partners such as EZH1, DNMT3B etc, the expression of PHF19 (a PRC2 complex co-factor) was highly upregulated in EZH2 compared to JARID2 pull-down assay. This finding, in addition to what is known in the literature [ 54 , 69 , 70 , 72 ], it is presumable that in women with endometriosis, FOXP3/miR-155, in conjunction with PHF19, co-localizes with the PRC2 complex to promote its interaction and function with its targets. This leads to the increased H3K27me3 deposition thus modulating gene transcription.…”

“…PHF19 has also been deemed to play a role in the switch from proliferative to invasive states in melanoma cells [ 71 ]. Thus there are studies suggesting targeting PHF19 as an alternate strategy to inhibit EZH2 [ 72 ]. This study found that PHF19 mRNA expression was significantly upregulated in cells treated with endo PF ( Figure 8 ).…”