Review
Long noncoding RNAs and prostate carcinogenesis: the missing ‘linc’?

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Highlights

Long noncoding RNAs (lncRNAs) are rapidly becoming essential pieces in the cancer puzzle. Our understanding of their functional capabilities is in its infancy. One certain fact, however, is that their molecular interactions extend beyond chromatin complexes into diverse biological processes. In prostate cancer, aberrant expression of lncRNAs is associated with disease progression. Overexpression of oncogenic lncRNAs promotes tumor-cell proliferation and metastasis through chromatin looping and distal engagement with the androgen receptor, antisense gene regulation, alternative splicing, and impeding DNA repair. Several lncRNAs, such as prostate cancer antigen 3 (PCA3), prostate cancer gene expression marker 1 (PCGEM1), and prostate cancer associated ncRNA transcript 1 (PCAT1), are highly prostate-specific, posing as attractive biomarkers. Herein we review the mechanisms of action of lncRNAs in prostate carcinogenesis and their potential clinical utility for disease.

Section snippets

The emergence of lncRNAs in cancer cell biology

Recent advances in next-generation sequencing technologies have greatly enhanced our understanding of the human transcriptome, and it has been determined that over 90% of the genome is actively transcribed 1, 2. Yet, only a minority of transcripts are translated into proteins. The noncoding portion, initially thought of as the ‘dark matter’ of the genome, thus represents a significant majority of transcriptional output. Noncoding RNAs (ncRNAs) are broadly divided into short (<200 nt) and long

Function 1: lncRNAs as mediators of enhancer-promoter looping in PCa

The androgen receptor (AR; see Glossary) is a transcription factor that is fundamental for growth and survival of prostate cells and thus has a key role in prostate carcinogenesis. AR blockade almost always induces tumor regression and is the first-line treatment for disseminated disease. However, castration-resistant PCa (CRPC) invariably develops and represents the lethal stage of the disease. There is therefore much interest in understanding the mechanisms underlying progression to

Risk prediction: lncRNAs in key PCa susceptibility zone 8q24

Genome-wide association studies have identified a large proportion of cancer-associated genetic variants or single-nucleotide polymorphisms (SNPs) that map to noncoding genomic intervals [53]. Many of these noncoding SNPs are located within enhancers; however, others are found to reside within nc-genes [54]. An analysis of 33 SNPs that are independently associated with PCa risk in European populations identified eight SNPs that localize to lnc-genes, suggesting a possible enrichment of

Concluding remarks and future perspectives

The field of lncRNA cancer biology is undoubtedly only just beginning. There is strong evidence of a major role for lncRNAs in PCa, with several hundred lncRNAs already identified as being aberrantly expressed. The challenge now and in the future is to tease out the truly oncogenic, functionally relevant lncRNAs. Only in doing this can the true biologic significance of lncRNAs in PCa carcinogenesis be realized. Some of the most illuminating findings to come will surely be in our greater

Acknowledgments

We gratefully acknowledge funding from the Irish Cancer Society, the Prostate Cancer Foundation, the Health Research Board, and Movember.

Glossary

Androgen receptor (AR)
a member of the steroid-hormone family of nuclear receptors. Upon binding the hormone ligand (testosterone or dihydrotestosterone), the AR dissociates from accessory proteins, translocates to the nucleus, and dimerizes, stimulating transcription of androgen-responsive genes by interacting with an androgen response element (ARE).
Biochemical recurrence (BCR)
a rise in prostate-specific antigen (PSA) of ≥0.2 ng/ml following radical prostatectomy, or consecutive rises in PSA

References (82)

  • A. Haese

    Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy

    Eur. Urol.

    (2008)
  • M. Auprich

    Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging

    Eur. Urol.

    (2011)
  • G.H. Leyten

    Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer

    Eur. Urol.

    (2014)
  • S. Ren

    Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 derived miniRNA as a novel plasma-based biomarker for diagnosing prostate cancer

    Eur. J. Cancer

    (2013)
  • L. Salmena

    A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?

    Cell

    (2011)
  • U.A. Orom et al.

    Long noncoding RNAs usher in a new era in the biology of enhancers

    Cell

    (2013)
  • E.P. Consortium

    Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

    Nature

    (2007)
  • S. Djebali

    Landscape of transcription in human cells

    Nature

    (2012)
  • F. O’Kelly

    MicroRNAs as putative mediators of treatment response in prostate cancer

    Nat. Rev. Urol.

    (2012)
  • M.R. Fabian et al.

    The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC

    Nat. Struct. Mol. Biol.

    (2012)
  • G. St Laurent

    Intronic RNAs constitute the major fraction of the non-coding RNA in mammalian cells

    BMC Genomics

    (2012)
  • P.J. Volders

    LNCipedia: a database for annotated human lncRNA transcript sequences and structures

    Nucleic Acids Res.

    (2013)
  • T. Derrien

    The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression

    Genome Res.

    (2012)
  • M. Guttman

    Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals

    Nature

    (2009)
  • A.L. Brunner

    Transcriptional profiling of long non-coding RNAs and novel transcribed regions across a diverse panel of archived human cancers

    Genome Biol.

    (2012)
  • V.A. Moran

    Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs

    Nucleic Acids Res.

    (2012)
  • J.T. Lee

    Epigenetic regulation by long noncoding RNAs

    Science

    (2012)
  • E.A. Gibb

    The functional role of long non-coding RNA in human carcinomas

    Mol. Cancer

    (2011)
  • P. Ji

    MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer

    Oncogene

    (2003)
  • R.A. Gupta

    Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis

    Nature

    (2010)
  • Z. Du

    Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer

    Nat. Struct. Mol. Biol.

    (2013)
  • Z. Kan

    Diverse somatic mutation patterns and pathway alterations in human cancers

    Nature

    (2010)
  • J.R. Prensner

    Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression

    Nat. Biotechnol.

    (2011)
  • L. Yang

    lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs

    Nature

    (2013)
  • V. Srikantan

    PCGEM1, a prostate-specific gene, is overexpressed in prostate cancer

    Proc. Natl. Acad. Sci. U.S.A.

    (2000)
  • G. Petrovics

    Elevated expression of PCGEM1, a prostate-specific gene with cell growth-promoting function, is associated with high-risk prostate cancer patients

    Oncogene

    (2004)
  • S. Chung

    Association of a novel long non-coding RNA in 8q24 with prostate cancer susceptibility

    Cancer Sci.

    (2011)
  • A.M. Schmitt et al.

    Gene regulation: Long RNAs wire up cancer growth

    Nature

    (2013)
  • K.C. Wang

    A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression

    Nature

    (2011)
  • F. Lai

    Activating RNAs associate with Mediator to enhance chromatin architecture and transcription

    Nature

    (2013)
  • D.D. Licatalosi et al.

    RNA processing and its regulation: global insights into biological networks

    Nat. Rev. Genet.

    (2010)

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