Abstract
BackgroundETS 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.Methodology/Principal FindingsWe 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., ERGhigh, ESE1high, ESE3low and NoETS tumors) were identified on the basis of their ETS expression status and showed distinct transcriptional and biological features. ERGhigh and ESE3low 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/SignificanceThese 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.
Highlights
Cancer of the prostate is the most common cancer and a leading cause of cancer death in western countries [1]
To gain a comprehensive view of the ETS transcriptional network in prostate cancer, we examined the expression of the ETS gene family in microarray datasets from primary prostate cancer (n = 59) and normal prostate (n = 14) clinical samples
We previously showed that ESE3, that is expressed in normal prostate epithelial cells, negatively affected proliferation and survival of prostate cancer cells and proposed that it acted as a tumor suppressor [11]
Summary
Cancer of the prostate is the most common cancer and a leading cause of cancer death in western countries [1]. ETS transcription factors have emerged as important elements in prostate tumorigenesis due to the finding of recurrent translocations involving ETS genes, the most frequent being the TMPRSS2: ERGa gene fusion leading to over-expression of full length ERG [2,3,4]. Most ETS factors, like those translocated in prostate cancer, promote cell proliferation, survival and transformation, while others act as tumor suppressors [10]. We found that the epithelial-specific ETS factor ESE3 was frequently down-regulated in prostate cancer, negatively affected cell proliferation and survival, and acted as tumor suppressor in prostate epithelial cells [11]. 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. The biological impact of ETS factors in prostate tumorigenesis is still debated
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