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Functional roles of antisense enhancer RNA for promoting prostate cancer progression.

ABSTRACT: Rationale: Enhancer RNA (eRNA) bi-directionally expresses from enhancer region and sense eRNA regulates adjacent mRNA in cis and in trans. However, it has remained unclear whether antisense eRNAs in different direction are functional or merely a reflection of enhancer activation. Methods: Strand-specific, ribosome-minus RNA sequencing (RNA-seq) were performed in AR positive prostate cancer cells. RNA-seq, GRO-seq, ChIP-seq, 4C-seq and DNA-methylation-seq that published in our and other labs were re-analyzed to define bi-directional enhancer RNA and DNA methylation regions. Molecular mechanisms were demonstrated by 3C, ChIP, ChIRP, CLIP, RT-PCR and western blot assays. The biological functions of antisense-eRNA were assessed using mice xenograft model and RT-PCR analysis in human tissues. Results: In this study, we identified that antisense eRNA was regulated by androgen receptor (AR) activity in prostate cancer cells. Antisense eRNA negatively regulated antisense ncRNA in AR-related target genes' loci, through recruiting DNMT1 on the antisense enhancer in the gene-ending regions and elevating DNA methylation. Importantly, the chromatin exhibited a double looping manner that facilitated sense-eRNA to promoter and antisense-eRNA to gene-ending region in cis. Depletion of antisense eRNA impaired its neighbor mRNA expression, cancer growth and invasion. The expressions of antisense eRNA were correlated with biochemical recurrence and clinical marker PSA's levels in patients' tissues. Conclusions: The findings indicated that antisense eRNA was a functional RNA and may be a novel target that when suppressed improved prostate cancer therapy and diagnosis. New chromatin interaction among enhancer, promoter and gene-ending region might provide new insight into the spatiotemporal mechanism of the gene transcription and acting of bi-directional eRNAs.

SUBMITTER: Pan CW

PROVIDER: S-EPMC7778597 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Functional roles of antisense enhancer RNA for promoting prostate cancer progression.

Pan Chun-Wu CW Wen Simeng S Chen Lei L Wei Yulei Y Niu Yuanjie Y Zhao Yu Y

Theranostics 20210101 4

<b>Rationale:</b> Enhancer RNA (eRNA) bi-directionally expresses from enhancer region and sense eRNA regulates adjacent mRNA in cis and in trans. However, it has remained unclear whether antisense eRNAs in different direction are functional or merely a reflection of enhancer activation. <b>Methods:</b> Strand-specific, ribosome-minus RNA sequencing (RNA-seq) were performed in AR positive prostate cancer cells. RNA-seq, GRO-seq, ChIP-seq, 4C-seq and DNA-methylation-seq that published in our and o ...[more]

PMID: 33408781

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Project description:BackgroundProstate cancer is one of the most common malignant cancers with the second highest global rate of mortality in men. During the early stages of disease progression, tumour growth is local and androgen-dependent. Despite treatment, a large percentage of patients develop androgen-independent prostate cancer, which often results in metastases, a leading cause of mortality in these patients. Our previous work on the RNA-binding protein Staufen1 demonstrated its novel role in cancer biology, and in particular rhabdomyosarcoma tumorigenesis. To build upon this work, we have focused on the role of Staufen1 in other forms of cancer and describe here the novel and differential roles of Staufen1 in prostate cancer.MethodsUsing a cell-based approach, three independent prostate cancer cell lines with different characteristics were used to evaluate the expression of Staufen1 in human prostate cancer relative to control prostate cells. The functional impact of Staufen1 on several key oncogenic features of prostate cancer cells including proliferation, apoptosis, migration and invasion were systematically investigated.ResultsWe show that Staufen1 levels are increased in all human prostate cancer cells examined in comparison to normal prostate epithelial cells. Furthermore, Staufen1 differentially regulates growth, migration, and invasion in the various prostate cancer cells assessed. In LNCaP prostate cancer cells, Staufen1 regulates cell proliferation through mTOR activation. Conversely, Staufen1 regulates migration and invasion of the highly invasive, bone metastatic-derived, PC3 prostate cells via the activation of focal adhesion kinase.ConclusionsCollectively, these results show that Staufen1 has a direct impact in prostate cancer development and further demonstrate that its functions vary amongst the prostate cancer cell types. Accordingly, Staufen1 represents a novel target for the development of much-needed therapeutic strategies for prostate cancer.

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Functional roles of antisense enhancer RNA for promoting prostate cancer progression.

Publications

Functional roles of antisense enhancer RNA for promoting prostate cancer progression.

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