The long non-coding RNA PCGEM1 is regulated by androgen receptor activity in vivo.

Abhijit Parolia,Yuwei Wang,Pier-Luc Clermont,Fan Mo,Yuzhuo Wang,Colin Collins,Hui Hsuan Liu,Nur Ridzwan Nur Saidy,Hui Xue,Hongwei Cheng,Dong Lin,Francesco Crea,Varune Rohan Ramnarine,Cheryl D Helgason

doi:10.1186/s12943-015-0314-4

Abhijit Parolia, Yuwei Wang + Show 12 more

Open Access

https://doi.org/10.1186/s12943-015-0314-4

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Abstract

BackgroundLong non-coding RNAs (lncRNAs) can orchestrate oncogenic or tumor-suppressive functions in cancer biology. Accordingly, PCGEM1 and PRNCR1 were implicated in progression of prostate cancer (PCa) as transcriptional co-regulators of the androgen receptor (AR). However, these findings were recently refuted asserting that neither gene physically binds to the AR. Despite evidence for differing AR transcriptional programs in vivo and in vitro, studies investigating AR-regulation of these genes hitherto have only been conducted in vitro. Here, we further examine the relevance of PCGEM1 and PRNCR1 in PCa, and their relationship with AR signaling, using patient-derived xenograft models.FindingsRNA sequencing of two distinct androgen-dependent models shows PCGEM1 to be considerably expressed, while PRNCR1 showed scant basal expression. PCGEM1 was sharply down-regulated following castration and up-regulated upon AR activation in vivo. However, we found no parallel evidence following AR stimulation in vitro. A PCGEM1-associated gene expression signature (PES) was significantly repressed in response to androgen ablation therapy and in hormone-refractory versus hormone-naïve PCa patients. Furthermore, we found PCGEM1 was uniformly distributed in PCa cell nucleus and cytoplasm which remained unaltered upon AR transcriptional activation. PCGEM1 was up-regulated in primary PCa but not in metastasized PCa. Accordingly, the PES was significantly down-regulated in advanced and higher grade PCa patients from multiple independent studies.ConclusionOur results demonstrate PCGEM1 as an in vivo androgen-regulated transcript with potential nuclear and/or cytoplasmic function(s). Importantly, the clinical expression profile of PCGEM1 implicates it in the early stages of PCa warranting further research in this direction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0314-4) contains supplementary material, which is available to authorized users.

Highlights

In recent years, long non-coding RNAs have emerged as major contributors to cellular homeostasis as well as initiation and progression of numerous diseases [1], including prostate cancer (PCa) [2]
The clinical expression profile of prostate cancer gene expression marker 1 (PCGEM1) implicates it in the early stages of PCa warranting further research in this direction
We described PCAT18 as a mediator of metastatic progression based on expression profiling of our Parolia et al Molecular Cancer (2015) 14:46 patient-derived PCa xenograft models from the Living Tumor Laboratory (LTL) [13]

Summary

Introduction

Long non-coding RNAs (lncRNAs) have emerged as major contributors to cellular homeostasis as well as initiation and progression of numerous diseases [1], including prostate cancer (PCa) [2]. We set out to investigate whether PCGEM1 and PRNCR1 are relevant in PCa and/or regulated by AR using our LTL patient-derived xenograft PCa models. AR regulates expression of PCGEM1 in vivo We performed surgical castration (androgen ablation) of mice bearing the LTL-331 PCa xenograft.

Results

Conclusion