Is Long Noncoding RNA a Culprit in Prostate Cancer?

from Oncotherapy Network by Bryant Furlow –

Noncoding RNA appears to be involved in the epigenetic regulation of prostate cancer, according to findings published in Nature Genetics.

“Our research looked at genetic variations associated with prostate cancer and we found that about half of those genetic variations may function through noncoding genes rather than the protein-coding genes,” said senior study coauthor Housheng Hansen He, PhD, of the Princess Margaret Cancer Centre, University Health Network, in Toronto, Ontario, Canada, in an interview. “Noncoding RNA have very important functions in driving prostate cancer development and progression.”

The vast majority of the human genome does not encode proteins and was long dismissed as “junk” DNA—meaningless detritus that had accumulated over millions of years. But epigeneticists like Dr. He, are finding that the noncoding RNA expressed by these regions actually play important and complex regulatory roles for genes in the protein-encoding exome. In other words, noncoding RNA genes function as tuning dials and switches for the activation and regulation of other, protein-encoding genes.

Little is known about how exactly the 123 genomic risk regions associated with prostate cancer contribute to tumor development, Dr. He noted. But the new study suggests that many of these regions involve epigenetic regulatory roles for noncoding RNA.

Dr. He and colleagues used integrative analyses of noncoding RNA transcriptome, genome, and single nucleotide polymorphisms from prostate tumor genome-wide association studies to identify candidate long noncoding RNAs (lncRNAs) associated with prostate cancer progression.

They then more closely studied the “top hit” among these candidate lncRNAs, PCAT1, which was previously shown to be elevated in patients with prostate cancer and to modulate several prostate cancer tumorigenesis pathways, including BRCA2 and MYC.

The team found that PCAT1 apparently “functions as a kind of glue” that binds protein complexes together, in order to epigenetically upregulate genes involved in tumorigenesis, Dr. He explained.

Identification of lncRNAs associated with prostate cancer risk

lncRNA

(a) DHSs encompassing one or more risk-associated SNPs are closer to protein-coding and lncRNA genes than genomic background. Shading corresponds to 95% confidence intervals. (b) A simplified diagram of the study approach. (c) List of the top 20 candidate lncRNA genes. Blue and white correspond to the presence or absence of each factor: risk SNP in promoter (Promoter), high intercellular functional correlation (IFC), eQTL with one or more risk SNPs (Cis-eQTL) and differential expression (DE). The score column shows a weighted summary of the binary states of the four factors. (d) Expression of PCAT1 in benign and tumor samples from two different studies59. The whiskers in each box plot indicate the range of the data, and the bar inside the box denotes the median enrichment score. (e) siRNA-mediated knockdown of PCAT1 significantly reduces proliferation of LNCaP, 22RV1 and VCaP cells. The bar plots show relative cell proliferation on day 6 after treatment with control siRNA (siCtrl) or two different siRNAs targeting PCAT1 (siPCAT1 1 and 2). Error bars, s.d. from four technical replicates. (f,g) Tumor growth and survival analysis in LNCaP C4-2 xenografts. Locked nucleic acid RNA (LNA-RNA) was used to deplete endogenous PCAT1 expression in LNCaP C4-2 cells. (f) Tumor volume was measured after tumor excision; error bars, s.d. from tumors in 12 mice per group. (g) Survival data for male mice (n = 12 per group) bearing LNCaP C4-2 cells were obtained from another batch of tumor inoculation. P values were calculated by Student’s t test in d, f and g and by one-way ANOVA in e: *P < 0.05, **P < 0.01.

A risk-associated single nucleotide polymorphism (SNP), rs7463708, modulates chromatin binding of ONECUT2 transcription factor, which the researchers found interacts with AR and the PCAT1 promoter in a manner that upregulates PCAT1 during prolonged androgen therapy.

The researchers plan next to similarly explore the functions of the other 44 genes.

The findings might hasten development of prognostic biomarkers for personalized treatment decision-making, Dr. He noted.

Source – Oncotherapy Network

Guo H, Ahmed M, Zhang F, Yao CQ, Li S, Liang Y, Hua J, Soares F, Sun Y, Langstein J, Li Y, Poon C, Bailey SD, Desai K, Fei T, Li Q, Sendorek DH, Fraser M, Prensner JR, Pugh TJ, Pomerantz M, Bristow RG, Lupien M, Feng FY, Boutros PC, Freedman ML, Walsh MJ, He HH. (2016) Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer. Nat Genet [Epub ahead of print]. [abstract]

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