An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression

By Jindan Yu, Jianjun Yu, R. Mani, Q. Cao, C. Brenner, Xuhong Cao, G. Wang, Longtao Wu, James Li, Ming Hu and 14 more. Cancer Cell, 2010

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SUMMARY While chromosomal rearrangements fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG occur in approximately 50% of prostate cancers, how the fusion products regulate prostate cancer remains unclear. Using chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq), we found that ERG disrupts androgen receptor (AR) signaling by inhibiting AR expression, binding to and inhibiting AR activity at gene-specific loci, and inducing repressive epigenetic programs via direct activation of the H3K27 methyltransferase EZH2, a Polycomb group protein. These findings provide a working model in which TMPRSS2-ERG plays a critical role in cancer progression by disrupting lineage-specific differentiation of the prostate and potentiating the EZH2-mediated de-differentiation program.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/dd776d9f93a206ef44253b05eb38626d587b1fb9

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Citations in the corpus

The Estrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer (2014, positive): “Using publicly available datasets 25 , we found that 28% of the intergenic ER α binding sites in the prostate cancer genome (from VCaP ER α and NCI-H660 cell lines) overlapped with the active histone marks tri-methylated lysine 4 of histone H3 (H3K4me3) and tri-methylated lysine 36 of histone H3…”
ChIPBase: a database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from ChIP-Seq data (2012, background): “GSM353636 Prostate cell lines, VCaP - NT AR (3) GSM353637 Prostate cell lines, VCaP - NT ERG (3) GSM353638 Prostate cell lines, VCaP - siERG AR (3) GSM353639 Prostate cell lines, VCaP - siERG ERG (3) GSM353640 Prostate cell lines, 22RV1 - no treat AR (3) GSM353641 Prostate cell lines, LnCaP - 10nm R”
Molecular genetics of prostate cancer: new prospects for old challenges. (2010, background): “Recent whole-genome chromatin immunoprecipitation analyses have shown that ERG can bind to AR downsteam target genes and disrupts AR signaling in prostate cancer cells through epigenetic silencing , consistent with a role in inhibiting prostate epithelial differentiation (Yu et al. 2010).”
Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. (2010, positive): “In addition, PcG proteins have been shown to be recruited to target genes by physically interacting with a number of chimeric fusion proteins involved in leukemia, such as PLZF-RARA and TMPRSS2-ERG (Figure 5D) (Boccuni et al., 2003; Boukarabila et al., 2009; Garcı́a-Cuéllar et al., 2001; Hemenway et”
Epigenetic Modifications as Therapeutic Targets (2010, background): “Thus, pharmacological disruption of ERG activity could reduce the EZH2 overexpression observed in cance”
The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis (2011, background): “These studies have pro- vided important insights into the upstream mechanisms which direct the transcriptional activities of the AR and identified a number of transcription factors which cooperate with or antagonize AR activity (Wang et al, 2007; Jia et al, 2008; Yu et al, 2010).”