ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer.
BACKGROUND
ETS transcription factors regulate important signaling pathways involved in cell differentiation and development in many tissues and have emerged as important players in prostate cancer. However, the biological impact of ETS factors in prostate tumorigenesis is still debated.


RESULTS
We performed an analysis of the ETS gene family using microarray data and real-time PCR in normal and tumor tissues along with functional studies in normal and cancer cell lines to understand the impact in prostate tumorigenesis and identify key targets of these transcription factors. We found frequent dysregulation of ETS genes with oncogenic (i.e., ERG and ESE1) and tumor suppressor (i.e., ESE3) properties in prostate tumors compared to normal prostate. Tumor subgroups (i.e., ERG(high), ESE1(high), ESE3(low) and NoETS tumors) were identified on the basis of their ETS expression status and showed distinct transcriptional and biological features. ERG(high) and ESE3(low) tumors had the most robust gene signatures with both distinct and overlapping features. Integrating genomic data with functional studies in multiple cell lines, we demonstrated that ERG and ESE3 controlled in opposite direction transcription of the Polycomb Group protein EZH2, a key gene in development, differentiation, stem cell biology and tumorigenesis. We further demonstrated that the prostate-specific tumor suppressor gene Nkx3.1 was controlled by ERG and ESE3 both directly and through induction of EZH2.


CONCLUSIONS
These findings provide new insights into the role of the ETS transcriptional network in prostate tumorigenesis and uncover previously unrecognized links between aberrant expression of ETS factors, deregulation of epigenetic effectors and silencing of tumor suppressor genes. The link between aberrant ETS activity and epigenetic gene silencing may be relevant for the clinical management of prostate cancer and design of new therapeutic strategies.
Kunderfranco
Paolo
P
Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
Mello-Grand
Maurizia
M
Cangemi
Romina
R
Pellini
Stefania
S
Mensah
Afua
A
Albertini
Veronica
V
Malek
Anastasia
A
Chiorino
Giovanna
G
Catapano
Carlo V
CV
Carbone
Giuseppina M
GM
D000368:Aged; D023102:Anoikis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D008875:Middle Aged; D008957:Models, Genetic; D063151:Polycomb Repressive Complex 2; D011471:Prostatic Neoplasms / Q000145:classification / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000071230:Transcriptional Regulator ERG; D025521:Tumor Suppressor Proteins / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D004268:DNA-Binding Proteins; C072312:ERG protein, human; D006657:Histones; D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D050783:Proto-Oncogene Proteins c-ets; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D025521:Tumor Suppressor Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine