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

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.

scholarly journals KDM6A-Mediated Expression of the Long Noncoding RNA DINO Causes TP53 Tumor Suppressor Stabilization in Human Papillomavirus 16 E7-Expressing Cells

2020 ◽  
Vol 94 (12) ◽  
Author(s):  
Surendra Sharma ◽  
Karl Munger
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Human Papillomavirus ◽  
Tumor Suppressor ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Metabolic Stress ◽  
Missing Link ◽  
Hpv16 E6 ◽  
Human Papillomavirus 16

ABSTRACT Human papillomavirus 16 (HPV16) E7 has long been known to stabilize the tumor suppressor TP53. However, the molecular mechanism of TP53 stabilization by HPV16 E7 has remained obscure, and this stabilization can occur independently of the 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, by 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 independently of RB1 degradation and E2F1 activation. Similar to what is seen with the adjacent CDKN1A locus, DINO expression is regulated by the histone demethylase KDM6A. DINO stabilizes TP53 in HPV16 E7-expressing cells, and as it is a TP53 transcriptional target, DINO levels further increase. As with expression of other oncogenes, such as adenovirus E1A or MYC, HPV16 E7-expressing cells are sensitized to cell death under conditions of metabolic stress, which in the case of E7 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 starvation or the antidiabetic drug metformin. Sensitivity of HPV16 E7-expressing cells to metabolic stress is rescued by DINO depletion. Moreover, DINO depletion decreases sensitivity to the DNA damage-inducing chemotherapy agent doxorubicin. This work identifies DINO as a critical mediator of TP53 stabilization and activation in HPV16 E7-expressing cells. IMPORTANCE Viral 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 cell death response of HPV16 E7-expressing cells to metabolic stress or DNA damage.

XIST: A Meaningful Long Noncoding RNA in NSCLC Process

2020 ◽  
Vol 26 ◽  
Author(s):  
Yujie Shen ◽  
Yexiang Lin ◽  
Kai Liu ◽  
Jinlan Chen ◽  
Juanjuan Zhong ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Critical Role ◽  
Biological Functions ◽  
Potential Therapeutic Target ◽  
Considerable Evidence ◽  
Lncrna Xist ◽  
Nsclc Patients ◽  
The Relationship

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.

scholarly journals The Novel Long Noncoding RNA TUSC7 Inhibits Proliferation by Sponging MiR-211 in Colorectal Cancer

2017 ◽  
Vol 41 (2) ◽  
pp. 635-644 ◽  
Author(s):  
Jian Xu ◽  
Rui Zhang ◽  
Jian Zhao
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Proliferation Rate ◽  
Expression Level ◽  
The Novel ◽  
Cell Proliferation Rate ◽  
Potential Tumor Suppressor

Background/Aims: The novel long noncoding RNA (lncRNA) tumor suppressor candidate 7 (TUSC7) has been reported as a potential tumor suppressor, while the functional role of TUSC7 is still unknown in colorectal cancer (CRC). Here, we characterized TUSC7 expression profile in CRC patients and investigated its biological function and potential molecular mechanism. Methods: RNA isolation, qRT-PCR, cell counter kit-8 assay, cell cycle assay, EdU assay, and western blot were performed. Statistical analyses were performed using SPSS 18.0 software and p value < 0.05 was considered as statistically significant. Results: In a cohort of CRC patients, we found TUSC7 was significantly downregulated in CRC tissues compared with adjacent non-tumor tissues (P < 0.01). Patients with high expression of TUSC7 had better survival than those with low expression of TUSC7 (HR = 0.342, 95% CI: 0.120-0.972, P = 0.044). Cell count kit 8 and EdU assays showed that ectopic expression of TUSC7 in HCT116 and SW480 cells significantly inhibited cell proliferation rate. After silence of TUSC7 with small interfering RNA, cell proliferation rate increased. Flow cytometry analyses revealed cycles were arrested at G1 phase after TUSC7 overexpression. We found there were 2 binding sites of miR-211-3p within the sequence of TUSC7 and TUSC7 expression level was negatively correlated with miR-211-3p. TUSC7 overexpression increased the expression level of CDK6, which is a downstream target of miR-211-3p, in both RNA and protein level. Furthermore, luciferase reporter assay indicated that TUSC7 could sponge miR-211-3p. Conclusion: To summary, we demonstrated that TUSC7 is a potential tumor suppressor in CRC, and TUSC7 could inhibit CRC cell proliferation by completely sponging miR-211-3p.

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

2014 ◽  
Author(s):  
Guijie Guo ◽  
Qingzheng Kang ◽  
Qinghuang Chen ◽  
Ouyang Jing ◽  
Jilong Chen
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Critical Role ◽  
Cellular Transformation

scholarly journals Long Noncoding RNA PVT1 Promotes Prostate Cancer Metastasis by Increasing NOP2 Expression via Targeting Tumor Suppressor MicroRNAs

2020 ◽  
Vol Volume 13 ◽  
pp. 6755-6765 ◽  
Author(s):  
Feng Sun ◽  
Ke Wu ◽  
Zhixian Yao ◽  
Xingyu Mu ◽  
Zhong Zheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Cancer Metastasis ◽  
Prostate Cancer Metastasis

scholarly journals Silencing of Long Noncoding RNA Nespas Aggravates Microglial Cell Death and Neuroinflammation in Ischemic Stroke

Stroke ◽  
2019 ◽  
Vol 50 (7) ◽  
pp. 1850-1858 ◽  
Author(s):  
Yiming Deng ◽  
Duanduan Chen ◽  
Luyao Wang ◽  
Feng Gao ◽  
Bo Jin ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Noncoding Rnas ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Oxygen Glucose Deprivation ◽  
Cerebral Artery Occlusion

Background and Purpose— Ischemic stroke is one of the leading causes of morbidity and mortality worldwide and a major cause of long-term disability. Recently, long noncoding RNAs have been revealed, which are tightly associated with several human diseases. However, the functions of long noncoding RNAs in ischemic stroke still remain largely unknown. In the current study, for the first time, we investigated the role of long noncoding RNA Nespas in ischemic stroke. Methods— We used in vivo models of middle cerebral artery occlusion and in vitro models of oxygen-glucose deprivation to illustrate the effect of long noncoding RNA Nespas on ischemic stroke. Results— We found expression of Nespas was significantly increased in ischemic cerebral tissues and oxygen-glucose deprivation–treated BV2 cells in a time-dependent manner. Silencing of Nespas aggravated middle cerebral artery occlusion operation–induced IR injury and cell death. In addition, proinflammatory cytokine production and NF-κB (nuclear factor-κB) signaling activation were inhibited by Nespas overexpression. TAK1 (transforming growth factor-β–activated kinase 1) was found to directly interact with Nespas, and TAK1 activation was significantly suppressed by Nespas. At last, we found Nespas-inhibited TRIM8 (tripartite motif 8)-induced K63-linked polyubiquitination of TAK1. Conclusions— We showed that Nespas played anti-inflammatory and antiapoptotic roles in cultured microglial cells after oxygen-glucose deprivation stimulation and in mice after ischemic stroke by inhibiting TRIM8-related K63-linked polyubiquitination of TAK1.

scholarly journals α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation

2017 ◽  
Vol 114 (5) ◽  
pp. 1183-1188 ◽  
Author(s):  
Seong Su Kang ◽  
Zhentao Zhang ◽  
Xia Liu ◽  
Fredric P. Manfredsson ◽  
Li He ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Lewy Bodies ◽  
Cell Loss ◽  
Dominant Negative ◽  
Dependent Manner ◽  
Ph Domain ◽  
Dopaminergic Cell ◽  
Neuroprotective Actions

The abnormal aggregation of fibrillar α-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson’s disease. However, the molecular mechanisms regulating α-synuclein pathological effects are incompletely understood. Here we show that α-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylation-dependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. α-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn. A pleckstrin homology (PH) domain in PIKE-L directly binds α-synuclein and antagonizes its aggregation. Accordingly, PIKE-L overexpression decreases dopaminergic cell death elicited by 1-methyl-4-phenylpyridinium (MPP+), whereas PIKE-L knockdown elevates α-synuclein oligomerization and cell death. The overexpression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or α-synuclein induces greater dopaminergic cell loss and more severe motor defects in PIKE-KO and Fyn-KO mice than in wild-type mice, and these effects are attenuated by the expression of dominant-negative AMPK. Hence, our findings demonstrate that α-synuclein neutralizes PIKE-L’s neuroprotective actions in synucleinopathies, triggering dopaminergic neuronal death by hyperactivating AMPK.

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

2019 ◽  
Vol 11 ◽  
pp. 175883591987464 ◽  
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.

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

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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