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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS
Paula Paulo1, Franclim R Ribeiro, Joana Santos
1Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
Abstract:
This work aimed to evaluate whether ETS transcription factors frequently involved in rearrangements in prostate carcinomas (PCa), namely ERG and ETV1, regulate specific or shared target genes. We performed differential expression analysis on nine normal prostate tissues and 50 PCa enriched for different ETS rearrangements using exon-level expression microarrays, followed by in vitro validation using cell line models. We found specific deregulation of 57 genes in ERG-positive PCa and 15 genes in ETV1-positive PCa, whereas deregulation of 27 genes was shared in both tumor subtypes. We further showed that the expression of seven tumor-associated ERG target genes (PLA1A, CACNA1D, ATP8A2, HLA-DMB, PDE3B, TDRD1, and TMBIM1) and two tumor-associated ETV1 target genes (FKBP10 and GLYATL2) was significantly affected by specific ETS silencing in VCaP and LNCaP cell line models, respectively, whereas the expression of three candidate ERG and ETV1 shared targets (GRPR, KCNH8, and TMEM45B) was significantly affected by silencing of either ETS. Interestingly, we demonstrate that the expression of TDRD1, the topmost overexpressed gene of our list of ERG-specific candidate targets, is inversely correlated with the methylation levels of a CpG island found at -66 bp of the transcription start site in PCa and that TDRD1 expression is regulated by direct binding of ERG to the CpG island in VCaP cells. We conclude that ETS transcription factors regulate specific and shared target genes and that TDRD1, FKBP10, and GRPR are promising therapeutic targets and can serve as diagnostic markers for molecular subtypes of PCa harboring specific fusion gene rearrangements.
Insights
ETS transcription factors ERG and ETV1 regulate distinct and overlapping genes in prostate cancer (PCa). TDRD1, FKBP10, and GRPR show promise as diagnostic markers and therapeutic targets for PCa subtypes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer (PCa) often involves rearrangements of ETS transcription factors, particularly ERG and ETV1.
- Understanding the target genes regulated by these ETS factors is crucial for PCa subtyping and targeted therapies.
Purpose of the Study:
- To determine if ERG and ETV1 regulate specific or shared target genes in PCa.
- To identify potential diagnostic markers and therapeutic targets based on ETS gene regulation.
Main Methods:
- Differential gene expression analysis using exon-level microarrays on normal prostate tissues and PCa samples.
- In vitro validation of target gene regulation using cell line models with ETS silencing.
- Analysis of gene expression correlation with DNA methylation for TDRD1.
Main Results:
- Identified 57 ERG-specific, 15 ETV1-specific, and 27 shared deregulated genes in PCa.
- Validated seven ERG targets (e.g., TDRD1) and two ETV1 targets (e.g., FKBP10) using gene silencing.
- Demonstrated ERG directly binds to a CpG island regulating TDRD1 expression, showing an inverse correlation with methylation.
Conclusions:
- ETS transcription factors ERG and ETV1 regulate both specific and shared gene sets in prostate cancer.
- TDRD1, FKBP10, and GRPR are identified as promising therapeutic targets and diagnostic markers for ETS-rearranged PCa subtypes.
