Long Noncoding RNAs: Emerging Stars in Gene Regulation, Epigenetics and Human Disease

Bhan, Arunoday; Mandal, Subhrangsu S.

doi:10.1002/cmdc.201300534

Cited by 246 publications

(188 citation statements)

References 276 publications

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“…Using the most advanced sequencing platforms and algorithms for assembling transcripts from deep RNA-sequencing reads, it is estimated that there are ~20,000 distinct lncRNAs in humans (30). LncRNAs demonstrate unique profiles in different forms of human cancer, which serve as predictors of patient outcomes and reflect disease progression (31,32). It was recently identified …”

Section: Discussionmentioning

confidence: 99%

Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells

Chen¹,

Bian²,

Zhao³

et al. 2016

Oncology Letters

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Abstract. Programmed cell death protein 4 (PDCD4) has recently been demonstrated to be implicated in translation and transcription, and the regulation of cell growth. However, the mechanisms underlying PDCD4 function in glioma cells remain to be elucidated. The current study investigated the function and regulation of PDCD4 and the results demonstrated that the expression of PDCD4 was significantly reduced in glioma cells compared with normal cells. When PDCD4 was overexpressed in glioma cells, the proliferation rate and invasive capability of the cells greatly decreased, suggesting that PDCD4 functions as a tumor suppressor in this cell type. In addition, the histone modification status of the PDCD4 gene was analyzed, and chromatin immunoprecipitation assay identified a high density of histone 3 lysine 27 trimethylation on the promoter of PDCD4, which was associated with the long non-coding RNA, homeobox transcript antisense RNA (HOTAIR). The expression of HOTAIR was significantly increased in glioma cells compared with normal cells, and it exerted its function in a polycomb repressive complex 2-dependent manner. These results may provide novel approaches to therapeutically target PDCD4 and HOTAIR in patients with gliomas. IntroductionHuman gliomas are the most prevalent malignant neoplasms of the central nervous system, with an annual incidence of ~5/100,000 worldwide (1). Despite the use of aggressive surgery in combination with chemotherapy, biological therapy and radiotherapy, gliomas continue to be therapeutically challenging (2). For patients with glioblastoma, the relative 5-year survival rate is <5% (3). Novel therapies for the treatment of glioma are warranted; recent advances in the understanding of the molecular and biological nature of this disease may facilitate the development of successful therapeutics (4).PDCD4 protein was initially determined to be overexpressed during apoptosis, which subsequently suppresses tumorigenesis (5,6). Loss of PDCD4 expression is closely associated with the progression of a number of tumors, including glioblastomas (7), and kidney, ovarian and lung cancer (8-10). Low PDCD4 expression levels correlate with poor outcomes in patients with glioblastoma multiforme (11). The frequent loss of PDCD4 in glioblastoma multiforme is partly due to epigenetic silencing secondary to 5' cytosine-phosphate-guanine island methylation (12), in addition to overexpression of microRNA (miRNA)-21, which targets PDCD4 mRNA for degradation (13). Although several studies have examined PDCD4 in glioma, the detailed molecular mechanisms underlying the role of PDCD4 in glioma remain poorly understood.Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides, which are involved in various important events, including transcriptional, epigenetic and post-transcriptional regulation (14,15). A previous study profiled the lncRNA homeobox transcript antisense RNA (HOTAIR), and the results demonstrated that HOTAIR was closely correlated with poor prognosis, molecular ...

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Section: Discussionmentioning

confidence: 99%

Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells

Chen¹,

Bian²,

Zhao³

et al. 2016

Oncology Letters

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“…However, gene expression is also extensively regulated at the translational level, meaning that mRNA abundance alone does not fully present the expressional status. To measure gene expression at the protein-synthesis level, HTS has been expanded to ribosome footprint profiling, which detects actively translating mRNA fragments in vivo.. 16,17 As ncRNAs are actively involved in expression control at the translational level 18 and BC200 RNA (an ncRNA) is a known to inhibit translation, we speculated that ribosome profiling might allow us to gain insight into the in vivo role of BC200 RNA in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of BC200 RNA expression reduces cell migration and invasion by destabilizing mRNA for calcium-binding protein S100A11

et al. 2017

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Although BC200 RNA is best known as a neuron-specific non-coding RNA, it is overexpressed in various cancer cells. BC200 RNA was recently shown to contribute to metastasis in several cancer cell lines, but the underlying mechanism was not understood in detail. To examine this mechanism, we knocked down BC200 RNA in cancer cells, which overexpress the RNA, and examined cell motility, profiling of ribosome footprints, and the correlation between cell motility changes and genes exhibiting altered ribosome profiles. We found that BC200 RNA knockdown reduced cell migration and invasion, suggesting that BC200 RNA promotes cell motility. Our ribosome profiling analysis identified 29 genes whose ribosomal occupations were altered more than 2-fold by BC200 RNA knockdown. Many (> 30%) of them were directly or indirectly related to cancer progression. Among them, we focused on S100A11 (which showed a reduced ribosome footprint) because its expression was previously shown to increase cellular motility. S100A11 was decreased at both the mRNA and protein levels following knockdown of BC200 RNA. An actinomycin-chase experiment showed that BC200 RNA knockdown significantly decreased the stability of the S100A11 mRNA without changing its transcription rate, suggesting that the downregulation of S100A11 was mainly caused by destabilization of its mRNA. Finally, we showed that the BC200 RNAknockdown-induced decrease in cell motility was mainly mediated by S100A11. Together, our results show that BC200 RNA promotes cell motility by stabilizing S100A11 transcripts.

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“…lncRNAs are transcripts of >200 nucleotides and conventionally cannot be translated into proteins to participate in a large number of biological processes (8,9). However, recent studies hypothesized that a number of lncRNAs are key developmental regulators that are involved in cell homeostasis and proliferation (9,10). Notably, increasing numbers of studies are indicating that the abnormal expression of certain lncRNAs is associated with tumor growth, carcinogenesis or metastasis in a range of malignancies (11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of long non-coding RNA HOTAIR predicts a poor prognosis in patients with acute myeloid leukemia

Zheng

Chen

et al. 2015

Oncology Letters

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Abstract. The long non-coding RNA, HOX transcript antisense intergenic RNA (HOTAIR), has been indicated to have involvement in a number of cancers, however, its role in acute myeloid leukemia (AML) is unknown. The present study aimed to investigate the pattern of HOTAIR expression in AML and to evaluate its clinical significance in tumor progression. Quantitative polymerase chain reaction was performed to examine the HOTAIR expression in mononuclear cells from the bone marrow (BM) or peripheral blood specimens of 85 patients with newly diagnosed AML. The association of HOTAIR expression with the clinicopathological factors and prognosis of AML patients was statistically analyzed. The expression of HOTAIR was significantly upregulated in the AML patients compared with the healthy controls (mean expression value, 3.87±0.29 vs. 1.28±0.09; P<0.001), and markedly decreased in the patients post-treatment compared with pre-treatment (4.76±0.47 vs. 2.81±0.27; P<0.001). Moreover, high levels of HOTAIR were associated with higher white blood cell and BM blast counts (P<0.001 and P=0.001, respectively), and lower hemoglobin and platelet counts (P=0.007 and 0.001, respectively). Patients with a high level of HOTAIR expression had relatively poor overall survival (OS; 20.5 vs. 32.1 months, P=0.001) and relapse-free survival (21.5 vs. 33.6 months, P=0.001) times compared with those with a low level of HOTAIR expression. These data demonstrated that HOTAIR expression was upregulated in newly diagnosed AML patients and was associated with leukemic burden, and DFS and OS times. HOTAIR may represent a biomarker of a poor prognosis and is a potential therapeutic target for AML treatment.

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Long Noncoding RNAs: Emerging Stars in Gene Regulation, Epigenetics and Human Disease

Cited by 246 publications

References 276 publications

Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells

Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells

Knockdown of BC200 RNA expression reduces cell migration and invasion by destabilizing mRNA for calcium-binding protein S100A11

Overexpression of long non-coding RNA HOTAIR predicts a poor prognosis in patients with acute myeloid leukemia

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