Deciphering the function of non-coding RNAs in prostate cancer

The advent of next-generation sequencing methods is fuelling the discovery of multiple non-coding RNA transcripts with direct implication in cell biology and homeostasis. This new layer of biological regulation seems to be of particular importance in human pathogenesis, including cancer. The aberrant expression of ncRNAs is a feature of prostate cancer, as they promote tumor-suppressive or oncogenic activities, controlling multicellular events leading to carcinogenesis and tumor progression. From the small RNAs involved in the RNAi pathway to the long non-coding RNAs controlling chromatin remodeling, alternative splicing, and DNA repair, the non-coding transcriptome represents the significant majority of transcriptional output. As such, ncRNAs appear as exciting new diagnostic, prognostic, and therapeutic tools. However, additional work is required to characterize the RNA species, their functions, and their applicability to clinical practice in oncology.

Descriptive structure of a long non-coding RNA loci

lncRNA

Normally, lncRNAs are defined by their location accordingly to protein-coding genes in the vicinity. Antisense lncRNAs transcription initiate inside or 3′ of a protein-coding gene. They are transcribed in the opposite direction of protein-coding genes, overlapping any portion of a mRNA. Intronic lncRNAs initiate inside an intron of a protein-coding gene in either direction and terminate without overlapping exons. Bidirectional lncRNAs are transcripts that initiate in a divergent fashion from the promoter of a protein-coding gene; the precise distance cutoff that constitutes bidirectionality is not defined but is generally within ~100 base pairs. Intergenic lncRNAs (also termed large intervening non-coding RNAs or lincRNAs) are lncRNAs with separate transcriptional units from protein-coding genes. A key structural feature is that lincRNAs need to be 5 kb away from protein-coding genes. LincRNA genes are preferentially found within 10 kb of protein coding genes. These are defined as lncRNA transcripts that encompass a protein-coding gene within the “intron” of a lncRNA or as lncRNAs that overlap the intron of a protein coding gene.

lncRNA manipulation and consequential phenotypes in PCa

lncRNA

Biotype

Function

Phenotype

MEG3

lincRNA

Tumor suppressor

Promotes apoptosis by blocking BCL2, enhancing BAX and activating CASP3. Induces G0/G1 arrest by inhibiting CCND1

PCAT-29

lincRNA

Tumor suppressor

Androgen-regulated lincRNA. Suppresses PCa growth and metastases in chick chorioallantoic membrane assays. Identifies a subset of patients at higher risk for disease recurrence

NANOGP8

Pseudogene

Tumor suppressor

Decreases clonogenic and migratory potential of PCa cell lines ultimately impairs tumor development in vivo. NANOGP8 knockout increases sensitivity to docetaxel

DRAIC

lincRNA

Tumor suppressor

Activated by FOXA1 and NKX3-1, and repressed by AR, promoting downregulation of DRAIC during prostate cancer progression. Impairs cell invasion and migration, blocking the acquisition of fibroblast-like morphology in PCa cells

PCAT29

Tumor suppressor

Repressed by AR and induced by FOXA1. Migration and metastasis suppressor

GAS5

lncRNA/ Retained intron

Tumor suppressor

Involved in cellular growth arrest and apoptosis probably due to GAS5 encoded transcript mimics glucocorticoid response element (GRE). Hosts multiple snoRNA, containing multiple C/D box snoRNA genes in its introns

PCGEM1

lincRNA

Oncogene

Transcriptional regulator of key metabolic pathways in PCa cells acting as a coactivator for both c-Myc and AR, providing growth advantage. Also recruits PYGO2 and enhances selective looping of AR-bound enhancers to target gene promoters in PCa cells

PlncRNA-1

(CBR3-AS1)

Antisense

Oncogene

Regulates cell proliferation and apoptosis, by targeting AR

HOTAIR

Antisense

Oncogene

Androgen-repressed ncRNA upregulated following androgen deprivation therapies and in CRPC. Binds to the AR protein to block its interaction with MDM2, thereby preventing AR ubiquitination and protein degradation.Involved in cell growth and invasion

PRNCR1

lincRNA

Oncogene

Binds to the carboxyterminally acetylated AR on enhancers, and binds DOT1L. Promotes transcriptional activation by AR and ultimately cell proliferation

PCAT5

Oncogene

Implicated in cell growth, migration/invasion, colony-forming, and apoptosis. PCAT5 is a regulatory target of ERG

PCAT18

Oncogene

Involved in cell proliferation and apoptosis, migration and invasion. Activated by AR

TRPM2-AS

Antisense

Oncogene

Associated with poor clinical outcome. Depletion of TRPM2-AS induces apoptosis both in vitro and in vivo in androgen-independent PCa cells. Critical to maintain the cell cycle progession

Ramalho-Carvalho J, Fromm B, Henrique R, Jerónimo C. (2016) Deciphering the function of non-coding RNAs in prostate cancer. Cancer Metastasis Rev 35(2):235-62. [abstract]

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