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


RESULTS
RNA 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.


CONCLUSIONS
Our 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.
Honours Biotechnology Program, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada. aparolia@bccrc.ca.|Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. aparolia@bccrc.ca.|The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada. aparolia@bccrc.ca.
Abhijit
A
Parolia
Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. fcrea@bccrc.ca.|The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada. fcrea@bccrc.ca.|Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. fcrea@bccrc.ca.
Francesco
F
Crea
Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. hxue@bccrc.ca.|The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada. hxue@bccrc.ca.
Hui
H
Xue
Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. yuwang@bccrc.ca.|The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada. yuwang@bccrc.ca.
Yuwei
Y
Wang
The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada. fmo@prostatecentre.com.
Fan
F
Mo
The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada. vramnarine@prostatecentre.com.
Varune Rohan
VR
Ramnarine
Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. rliu@bccrc.ca.
Hui Hsuan
HH
Liu
Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. dlin@bccrc.ca.|The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada. dlin@bccrc.ca.|Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. dlin@bccrc.ca.
Dong
D
Lin
Honours Biotechnology Program, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada. rnursaidy@bccrc.ca.|Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. rnursaidy@bccrc.ca.
Nur Ridzwan Nur
NR
Saidy
Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. pclermont@bccrc.ca.|Interdisciplinary Oncology Program, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. pclermont@bccrc.ca.
Pier-Luc
PL
Clermont
Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. hcheng@bccrc.ca.|The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada. hcheng@bccrc.ca.
Hongwei
H
Cheng
The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada. ccollins@prostatecentre.com.
Colin
C
Collins
Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. ywang@bccrc.ca.|The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada. ywang@bccrc.ca.
Yuzhuo
Y
Wang
Experimental Therapeutics, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. chelgaso@bccrc.ca.|Department of Surgery, University of British Columbia, Vancouver, BC, Canada. chelgaso@bccrc.ca.
Cheryl D
CD
Helgason
D000728:Androgens / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics; D003593:Cytoplasm / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
C410798:AR protein, human; D000728:Androgens; C416084:PCGEM1 non-coding RNA, human; D062085:RNA, Long Noncoding; D011944:Receptors, Androgen