PHF19 mediated regulation of proliferation and invasiveness in prostate cancer cells.

Payal Jain,Pedro Vizan,Luciano Di Croce,Enrique Blanco,Cecilia Ballare

doi:10.7554/elife.51373

Abstract

The Polycomb-like protein PHF19/PCL3 associates with PRC2 and mediates its recruitment to chromatin in embryonic stem cells. PHF19 is also overexpressed in many cancers. However, neither PHF19 targets nor misregulated pathways involving PHF19 are known. Here, we investigate the role of PHF19 in prostate cancer cells. We find that PHF19 interacts with PRC2 and binds to PRC2 targets on chromatin. PHF19 target genes are involved in proliferation, differentiation, angiogenesis, and extracellular matrix organization. Depletion of PHF19 triggers an increase in MTF2/PCL2 chromatin recruitment, with a genome-wide gain in PRC2 occupancy and H3K27me3 deposition. Transcriptome analysis shows that PHF19 loss promotes deregulation of key genes involved in growth, metastasis, invasion, and of factors that stimulate blood vessels formation. Consistent with this, PHF19 silencing reduces cell proliferation, while promotes invasive growth and angiogenesis. Our findings reveal a role for PHF19 in controlling the balance between cell proliferation and invasiveness in prostate cancer.

Highlights

Polycomb group (PcG) proteins are transcriptional regulators involved in embryonic development, cell differentiation, and maintenance of cell identity
The opposite pattern was observed for MTF2 recruitment, with an increase in its levels in the absence of PHF19L, and a decrease to basal levels after PHF19L overexpression (Figure 4G). These results indicate that, in prostate cancer, PHF19L restricts an excessive occupancy of MTF2 at chromatin, suggesting that MTF2 could be responsible for the increase in PRC2 recruitment and activity following PHF19L depletion
PHF19S contains the Tudor domain that is implicated in binding to H3K36me3, but it lacks the predicted nuclear localization signals (Wang et al, 2004) and the C-terminal region reported to bind to the PRC2 complex (Ballareet al., 2012)

Summary

Introduction

Polycomb group (PcG) proteins are transcriptional regulators involved in embryonic development, cell differentiation, and maintenance of cell identity. PHF19 can promote proliferation in hepatocellular carcinoma, glioma, and ovarian cancers (Xu et al, 2015; Lu et al, 2018; Tao et al, 2018) and can induce glioblastoma progression, mediated by b-catenin (Deng et al, 2018) Despite these efforts to understand the role of PHF19 in different cancer models, a comprehensive analysis that identifies the genetic targets and pathways controlled by PHF19 has so far not been reported. Depletion of PHF19 causes upregulated MTF2/PCL2 expression and increased MTF2 recruitment to chromatin, along with a genome-wide gain in PRC2 occupancy and increased H3K27me deposition This in turn leads to transcriptional deregulation of key genes involved in the control of proliferation, angiogenesis, metastasis, and invasion. With the loss of PHF19, prostate cancer cells switch to a less proliferative but more aggressive phenotype

Results

Discussion

Materials and methods

Funding Funder