Abstract 3543: A long noncoding RNA plays a critical role in Bcr-Abl-mediated cellular transformation

Background: A number of studies have proposed that lncRNA XIST plays a role in the development and chemosensitivity of NSCLC. Besides, XIST may become a potential therapeutic target for NSCLC patients. The aim of this review is to reveal the biological functions and exact mechanisms of XIST in NSCLC. Methods: In this review, relevant researches involving in the relationship between XIST and NSCLC are collected through systematic retrieval of PubMed Results: XIST is an oncogene in NSCLC and is abnormally upregulated in NSCLC tissues. Considerable evidence has shown that XIST exerts a critical role in the proliferation, invasion, migration, apoptosis and chemosensitivity of NSCLC cells. XIST mainly functions as a ceRNA in NSCLC process, while XIST also functions at transcriptional levels. Conclusion: LncRNA XIST has potential to become a novel biomolecular marker of NSCLC and a therapeutic target for NSCLC.

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KDM6A mediated expression of the long noncoding RNA DINO causes TP53 tumor suppressor stabilization in Human Papillomavirus type 16 E7 expressing cells

10.1101/2020.01.01.892612 ◽

2020 ◽

Author(s):

Surendra Sharma ◽

Karl Munger

Keyword(s):

Cell Death ◽

Tumor Suppressor ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Critical Role ◽

Metabolic Stress ◽

Dominant Negative ◽

Missing Link ◽

Hpv16 E6 ◽

E6 And E7

ABSTRACTHPV16 E7 has long been noted to stabilize the TP53 tumor suppressor. However, the molecular mechanism of TP53 stabilization by HPV16 E7 has remained obscure and can occur independent of E2F regulated MDM2 inhibitor, p14ARF. Here, we report that the Damage Induced Noncoding (DINO) lncRNA (DINOL) is the missing link between HPV16 E7 and increased TP53 levels. DINO levels are decreased in cells where TP53 is inactivated, either by HPV16 E6, expression of a dominant negative TP53 minigene or by TP53 depletion. DINO levels are increased in HPV16 E7 expressing cells. HPV16 E7 causes increased DINO expression independent of RB1 degradation and E2F1 activation. Similar to the adjacent CDKN1A locus, DINO expression is regulated by the histone demethylase, KDM6A. DINO stabilizes TP53 in HPV16 E7 expressing cells and as a TP53 transcriptional target, DINO levels further increase. Similar to other oncogenes such as adenovirus E1A or MYC, HPV16 E7 expressing cells are sensitized to cell death under conditions of metabolic stress and in the case of E7, this has been linked to TP53 activation. Consistent with earlier studies, we show that HPV16 E7 expressing keratinocytes are highly sensitive to metabolic stress induced by the antidiabetic drug, metformin. Metformin sensitivity of HPV16 E7 expressing cells is rescued by DINO depletion. This work identifies DINO as a critical mediator TP53 stabilization and activation in HPV16 E7 expressing cells.IMPORTANCEViral oncoproteins, including HPV16 E6 and E7 have been instrumental in elucidating the activities of cellular signaling networks including those governed by the TP53 tumor suppressor. Our study demonstrates that the long noncoding RNA DINO is the long sought missing link between HPV16 E7 and elevated TP53 levels. Importantly, the TP53 stabilizing DINO plays a critical role in the predisposition of HPV16 E7 expressing cells to cell death under metabolic stress conditions from metformin treatment.

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Long noncoding RNA LSINCT5 promotes endometrial carcinoma cell proliferation, cycle, and invasion by promoting the Wnt/β-catenin signaling pathway via HMGA2

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919874649 ◽

2019 ◽

Vol 11 ◽

pp. 175883591987464 ◽

Cited By ~ 5

Author(s):

Hongye Jiang ◽

Yong Li ◽

Jie Li ◽

Xuyu Zhang ◽

Gang Niu ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Migration ◽

Endometrial Carcinoma ◽

Signaling Pathway ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Critical Role ◽

Migration And Invasion ◽

Migration Assay

Background: A review of the evidence has indicated the critical role of long noncoding RNA (lncRNA) LSINCT5 in a large number of human cancers. However, the mechanistic involvement of LSINCT5 in endometrial carcinoma (EC) is still unknown. Here the authors aim to characterize the expression status of LSINCT5 and elucidate its mechanistic relevance to EC. Methods: Relative expression of LSINCT5 and HMGA2 were quantified by a real-time polymerase chain reaction. SiRNAs were employed to specifically knockdown endogenous LSINCT5 in EC cells. Cell proliferation was measured with Cell Count Kit-8 kit (CCK-8, Dojindo, Kumamoto, Japan) and cell growth was assessed by a colony formation assay. The cell cycle was analyzed with propidium iodide (PI) staining. Apoptotic cells were determined by flow cytometry after Annexin V/PI double-staining. Cell migration was evaluated by a wound-healing assay, and cell invasion was assessed using a transwell migration assay. The protein levels of HMGA2, Wnt3a, p-β-catenin, c-myc, β-actin, and GAPDH were determined by western blot. Results: The authors observed positively correlated and aberrantly up-regulated LSINCT5 and HMGA2 in EC. LSINCT5 deficiency significantly inhibited cell proliferation, cell cycle progression, and induced apoptosis. Meanwhile, cell migration and invasion were greatly compromised by the LSINCT5 knockdown. LSINCT5 stabilized HMGA2, which subsequently stimulated activation of Wnt/β-catenin signaling and consequently contributed to the oncogenic properties of LSINCT5 in EC. Conclusions: Our data uncovered the oncogenic activities and highlighted the mechanistic contributions of the LSINCT5-HMGA2-Wnt/β-catenin signaling pathway in EC.

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A long noncoding RNA,LncMyoD, modulates chromatin accessibility to regulate muscle stem cell myogenic lineage progression

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2005868117 ◽

2020 ◽

Vol 117 (51) ◽

pp. 32464-32475

Author(s):

Anqi Dong ◽

Christopher B. Preusch ◽

Wai-Kin So ◽

Kangning Lin ◽

Shaoyuan Luan ◽

...

Keyword(s):

Stem Cells ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Target Genes ◽

Myogenic Differentiation ◽

Critical Role ◽

Chromatin Accessibility ◽

Mechanistic Study ◽

Muscle Stem Cells ◽

Myogenic Lineage

Epigenetics regulation plays a critical role in determining cell identity by controlling the accessibility of lineage-specific regulatory regions. In muscle stem cells, epigenetic mechanisms of how chromatin accessibility is modulated during cell fate determination are not fully understood. Here, we identified a long noncoding RNA,LncMyoD, that functions as a chromatin modulator for myogenic lineage determination and progression. The depletion ofLncMyoDin muscle stem cells led to the down-regulation of myogenic genes and defects in myogenic differentiation.LncMyoDexclusively binds with MyoD and not with other myogenic regulatory factors and promotes transactivation of target genes. The mechanistic study revealed that loss ofLncMyoDprevents the establishment of a permissive chromatin environment at myogenic E-box–containing regions, therefore restricting the binding of MyoD. Furthermore, the depletion ofLncMyoDstrongly impairs the reprogramming of fibroblasts into the myogenic lineage. Taken together, our study shows thatLncMyoDassociates with MyoD and promotes myogenic gene expression through modulating MyoD accessibility to chromatin, thereby regulating myogenic lineage determination and progression.

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Computational Approaches to Functionally Annotate Long Noncoding RNA (lncRNA)

10.20944/preprints202006.0116.v1 ◽

2020 ◽

Author(s):

Yashpal Ramakrishnaiah ◽

Levin Kuhlmann ◽

Sonika Tyagi

Keyword(s):

Machine Learning ◽

Ab Initio ◽

Long Noncoding Rna ◽

Functional Annotation ◽

Noncoding Rna ◽

Critical Role ◽

Structural Features ◽

Support Vector ◽

Learning Approaches ◽

Rna Interaction

Long noncoding RNA (lncRNA) are implicated in various genetic diseases and cancer, attributed to their critical role in gene regulation. RNA sequencing is used to capture their transcripts from certain cell types or conditions. For some studies, lncRNA interactions with other biomolecules have also been captured, which can give clues to their mechanisms of action. Complementary \textit{in silico} methods have been proposed to predict non-coding nature of transcripts and to analyze available RNA interaction data. Here we provide a critical review of such methods and identify associated challenges. Broadly, these can be categorized as reference-based and reference-free or \textit{ab initio}, with the former category of methods requiring a comprehensive annotated reference. The \textit{ab initio} methods can make use of machine learning classifiers that are trained on features extracted from sequences, making them suitable to predict novel transcripts, especially in non-model species. Machine learning approaches such as Logistic Regression, Support Vector Machines, Random Forest, and Deep Learning are commonly used. Initial approaches relied on basic sequential features to train the model, whereas the use of secondary structural features appears to be a promising approach for functional annotation. However, adding secondary features will result in model complexities, thus demanding an algorithm that can handle it and furthermore, considerably increasing the utilization of computation resources. Computational strategies combining identification and functional annotation which can be easily customized are currently lacking. These can be of immense value to accelerate research in this class of RNAs.

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Reciprocal modulation of long noncoding RNA EMS and p53 regulates tumorigenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2111409119 ◽

2022 ◽

Vol 119 (3) ◽

pp. e2111409119

Author(s):

Chenfeng Wang ◽

Yang Yang ◽

Xianning Wu ◽

Jingxin Li ◽

Kaiyue Liu ◽

...

Keyword(s):

Long Noncoding Rna ◽

Transcriptional Repression ◽

Messenger Rna ◽

Noncoding Rna ◽

Critical Role ◽

P53 Expression ◽

P53 Signaling ◽

Element Binding Protein ◽

Mrna Polyadenylation ◽

P53 Mrna

p53 plays a central role in tumor suppression. Emerging evidence suggests long noncoding RNA (lncRNA) as an important class of regulatory molecules that control the p53 signaling. Here, we report that the oncogenic lncRNA E2F1 messenger RNA (mRNA) stabilizing factor (EMS) and p53 mutually repress each other’s expression. EMS is negatively regulated by p53. As a direct transcriptional repression target of p53, EMS is surprisingly shown to inhibit p53 expression. EMS associates with cytoplasmic polyadenylation element-binding protein 2 (CPEB2) and thus, disrupts the CPEB2–p53 mRNA interaction. This disassociation attenuates CPEB2-mediated p53 mRNA polyadenylation and suppresses p53 translation. Functionally, EMS is able to exert its oncogenic activities, at least partially, via the CPEB2–p53 axis. Together, these findings reveal a double-negative feedback loop between p53 and EMS, through which p53 is finely controlled. Our study also demonstrates a critical role for EMS in promoting tumorigenesis via the negative regulation of p53.

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Long noncoding RNA functions as a direct transcriptional target of p73 and plays a critical role in suppression of cancer cell migration, invasion and metastasis via sponging of miR-1273g-3p

European Journal of Cancer ◽

10.1016/s0959-8049(20)31149-7 ◽

2020 ◽

Vol 138 ◽

pp. S30

Author(s):

A. Uboveja ◽

Y.K. Satija ◽

F. Siraj ◽

D. Saluja

Keyword(s):

Cell Migration ◽

Cancer Cell ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Critical Role ◽

Cancer Cell Migration ◽

Invasion And Metastasis ◽

Direct Transcriptional Target ◽

Transcriptional Target

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The long noncoding RNA LUCAT1 promotes colorectal cancer cell proliferation by antagonizing Nucleolin to regulate MYC expression

Cell Death and Disease ◽

10.1038/s41419-020-03095-4 ◽

2020 ◽

Vol 11 (10) ◽

Author(s):

Runliu Wu ◽

Liang Li ◽

Yang Bai ◽

Bowen Yu ◽

Canbin Xie ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Critical Role ◽

Multiple Cancer ◽

G Quadruplex

Abstract The long noncoding RNA (lncRNA) LUCAT1 was recently reported to be upregulated and to play an essential role in multiple cancer types, especially colorectal cancer (CRC), but the molecular mechanisms of LUCAT1 in CRC are mostly unreported. Here, a systematic analysis of LUACT1 expression is performed with data from TCGA database and clinic CRC samples. LUCAT1 is identified as a putative oncogene, which is significantly upregulated in CRC and is associated with poor prognosis. Loss of LUCAT1 restricts CRC proliferative capacities in vitro and in vivo. Mechanically, NCL is identified as the protein binding partner of LUCAT1 by using chromatin isolation by RNA purification coupled with mass spectrometry (ChIRP-MS) and RNA immunoprecipitation assays. We also show that NCL directly binds to LUCAT1 via its putative G-quadruplex-forming regions from nucleotides 717 to 746. The interaction between LUCAT1 and NCL interferes NCL-mediated inhibition of MYC and promote the expression of MYC. Cells lacking LUCAT1 show a decreased MYC expression, and NCL knockdown rescue LUCAT1 depletion-induced inhibition of CRC cell proliferation and MYC expression. Our results suggest that LUCAT1 plays a critical role in CRC cell proliferation by inhibiting the function of NCL via its G-quadruplex structure and may serve as a new prognostic biomarker and effective therapeutic target for CRC.

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A putative long noncoding RNA-encoded micropeptide maintains cellular homeostasis in pancreatic β-cells

10.1101/2020.05.12.091728 ◽

2020 ◽

Author(s):

Mark Li ◽

Fan Shao ◽

Qingwen Qian ◽

Wenjie Yu ◽

Zeyuan Zhang ◽

...

Keyword(s):

Insulin Secretion ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Cell Function ◽

Transmembrane Domain ◽

Critical Role ◽

Human Pancreas ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

ABSTRACTMicropeptides (microproteins) encoded by transcripts previously annotated as long noncoding RNA (IncRNAs) are emerging as important mediators of fundamental biological processes in health and disease. Here we applied two computational tools to identify putative micropeptides encoded by lncRNAs that are expressed in the human pancreas. We experimentally verified one such micropeptide encoded by a β-cell- and neural cell-enriched lncRNA TUNAR (also known as TUNA, HI-LNC78 or LINC00617). We named this highly conserved 48-amino-acid micropeptide Beta cell- and Neural cell-regulin (BNLN). BNLN contains a single-pass transmembrane domain and localized at the endoplasmic reticulum in pancreatic β-cells. Overexpression of BNLN lowered ER calcium levels, increased cytosolic calcium levels, and maintained ER homeostasis in response to high glucose challenge. To determine the physiological and pathological roles of BNLN, we assessed the BNLN expression in islets from mice fed with a high-fat diet and a regular diet, and found that BNLN is suppressed by diet-induced obesity (DIO). Conversely, overexpression of BNLN elevated glucose-stimulated insulin secretion in INS-1 cells. Lastly, BNLN overexpression enhanced insulin secretion in islets from lean and obese mice as well as from humans. Taken together, our study provides the first evidence that lncRNA-encoded micropeptides play a critical role in pancreatic β-cell function and provides a foundation for future comprehensive analyses of micropeptide function and pathophysiological impact on diabetes.

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