Dataset Information

A FTH1 gene:pseudogene:microRNA network regulates tumorigenesis in prostate cancer.

ABSTRACT: Non-coding RNAs play a vital role in diverse cellular processes. Pseudogenes, which are non-coding homologs of protein-coding genes, were once considered non-functional evolutional relics. However, recent studies have shown that pseudogene transcripts can regulate their parental transcripts by sequestering shared microRNAs (miRNAs), thus acting as competing endogenous RNAs (ceRNAs). In this study, we utilize an unbiased screen to identify the ferritin heavy chain 1 (FTH1) transcript and multiple FTH1 pseudogenes as targets of several oncogenic miRNAs in prostate cancer (PCa). We characterize the critical role of this FTH1 gene:pseudogene:miRNA network in regulating tumorigenesis in PCa, whereby oncogenic miRNAs downregulate the expression of FTH1 and its pseudogenes to drive oncogenesis. We further show that impairing miRNA binding and subsequent ceRNA crosstalk completely rescues the slow growth phenotype in vitro and in vivo. Our results also demonstrate the reciprocal regulation between the pseudogenes and intracellular iron levels, which are crucial for multiple physiological and pathophysiological processes. In summary, we describe an extensive gene:pseudogene network comprising multiple miRNAs and multiple pseudogenes derived from a single parental gene. The network could be regulated through multiple mechanisms to modulate iron storage in various signaling pathways, the deregulation of which results in PCa development and progression.

SUBMITTER: Chan JJ

PROVIDER: S-EPMC5829750 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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A FTH1 gene:pseudogene:microRNA network regulates tumorigenesis in prostate cancer.

Chan Jia Jia JJ Kwok Zhi Hao ZH Chew Xiao Hong XH Zhang Bin B Liu Chao C Soong Tuck Wah TW Yang Henry H Tay Yvonne Y

Nucleic acids research 20180201 4

Non-coding RNAs play a vital role in diverse cellular processes. Pseudogenes, which are non-coding homologs of protein-coding genes, were once considered non-functional evolutional relics. However, recent studies have shown that pseudogene transcripts can regulate their parental transcripts by sequestering shared microRNAs (miRNAs), thus acting as competing endogenous RNAs (ceRNAs). In this study, we utilize an unbiased screen to identify the ferritin heavy chain 1 (FTH1) transcript and multiple ...[more]

PMID: 29240947

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Project description:Pseudogenes are fossil relatives of genes. Pseudogenes have long been thought of as "junk DNAs", since they do not code proteins in normal tissues. Although most of the human pseudogenes do not have noticeable functions, ?20% of them exhibit transcriptional activity. There has been evidence showing that some pseudogenes adopted functions as lncRNAs and work as regulators of gene expression. Furthermore, pseudogenes can even be "reactivated" in some conditions, such as cancer initiation. Some pseudogenes are transcribed in specific cancer types, and some are even translated into proteins as observed in several cancer cell lines. All the above have shown that pseudogenes could have functional roles or potentials in the genome. Evaluating the relationships between pseudogenes and their gene counterparts could help us reveal the evolutionary path of pseudogenes and associate pseudogenes with functional potentials. It also provides an insight into the regulatory networks involving pseudogenes with transcriptional and even translational activities.In this study, we develop a novel approach integrating graph analysis, sequence alignment and functional analysis to evaluate pseudogene-gene relationships, and apply it to human gene homologs and pseudogenes. We generated a comprehensive set of 445 pseudogene-gene (PGG) families from the original 3,281 gene families (13.56%). Of these 438 (98.4% PGG, 13.3% total) were non-trivial (containing more than one pseudogene). Each PGG family contains multiple genes and pseudogenes with high sequence similarity. For each family, we generate a sequence alignment network and phylogenetic trees recapitulating the evolutionary paths. We find evidence supporting the evolution history of olfactory family (both genes and pseudogenes) in human, which also supports the validity of our analysis method. Next, we evaluate these networks in respect to the gene ontology from which we identify functions enriched in these pseudogene-gene families and infer functional impact of pseudogenes involved in the networks. This demonstrates the application of our PGG network database in the study of pseudogene function in disease context.

Dataset Information

A FTH1 gene:pseudogene:microRNA network regulates tumorigenesis in prostate cancer.

Publications

A FTH1 gene:pseudogene:microRNA network regulates tumorigenesis in prostate cancer.

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