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      Silencing of lncRNA XIST inhibits non-small cell lung cancer growth and promotes chemosensitivity to cisplatin

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          Abstract

          Long noncoding RNAs (lncRNAs) play critical roles in tumour progression and metastasis. Emerging evidence indicates that the lncRNA X inactive-specific transcript (XIST) is dysregulated in several tumor types, including non-small cell lung cancer (NSCLC). However, in NSCLC and other cancers the oncogenic mechanism of XIST remains incompletely understood. Here, we confirmed that XIST is upregulated in human NSCLC specimens, and is especially overexpressed in tumors previously treated with cisplatin (cis-diamminedichloroplatinum(II); DDP). In vitro, XIST knockdown inhibited NSCLC cell growth and promoted DDP chemosensitivity by stimulating apoptosis and pyroptosis. Moreover, XIST’s oncogenic effects and ability to promote DDP chemoresistance were largely related to its binding to the TGF-β effector SMAD2, which inhibited its translocation to the nucleus and prevented the transcription of p53 and NLRP3, crucial regulators of apoptosis and pyroptosis, respectively. Using DDP-resistant NSCLC cells, mouse xenograft studies verified the oncogenic function of XIST and its ability to inhibit programmed cell death, thereby mediating DDP chemoresistance. These findings suggest that XIST expression may serve as a novel biomarker to predict DDP treatment efficacy, and may help in the design of new therapies to circumvent DDP chemoresistance in NSCLC and other tumor types.

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          Most cited references28

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          Caspases in Cell Death, Inflammation, and Disease

          Caspases are an evolutionary conserved family of cysteine proteases that are centrally involved in cell death and inflammation responses. A wealth of foundational insight into the molecular mechanisms that control caspase activation has emerged in recent years. Important advancements include the identification of additional inflammasome platforms and pathways that regulate activation of inflammatory caspases; the discovery of gasdermin D as the effector of pyroptosis and interleukin (IL)-1 and IL-18 secretion; and the existence of substantial crosstalk between inflammatory and apoptotic initiator caspases. A better understanding of the mechanisms regulating caspase activation has supported initial efforts to modulate dysfunctional cell death and inflammation pathways in a suite of communicable, inflammatory, malignant, metabolic and neurodegenerative diseases. Here, we review current understanding of caspase biology with a prime focus on the inflammatory caspases, and outline important topics for future experimentation.
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            Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript.

            Alternative promoters within the same gene are a general phenomenon in gene expression. Mechanisms of their selective regulation vary from one gene to another and are still poorly understood. Here we show that in quiescent cells the mechanism of transcriptional repression of the major promoter of the gene encoding dihydrofolate reductase depends on a non-coding transcript initiated from the upstream minor promoter and involves both the direct interaction of the RNA and promoter-specific interference. The specificity and efficiency of repression is ensured by the formation of a stable complex between non-coding RNA and the major promoter, direct interaction of the non-coding RNA with the general transcription factor IIB and dissociation of the preinitiation complex from the major promoter. By using in vivo and in vitro assays such as inducible and reconstituted transcription, RNA bandshifts, RNA interference, chromatin immunoprecipitation and RNA immunoprecipitation, we show that the regulatory transcript produced from the minor promoter has a critical function in an epigenetic mechanism of promoter-specific transcriptional repression.
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              The non-coding Air RNA is required for silencing autosomal imprinted genes.

              In genomic imprinting, one of the two parental alleles of an autosomal gene is silenced epigenetically by a cis-acting mechanism. A bidirectional silencer for a 400-kilobase region that contains three imprinted, maternally expressed protein-coding genes (Igf2r/Slc22a2/Slc22a3) has been shown by targeted deletion to be located in a sequence of 3.7 kilobases, which also contains the promoter for the imprinted, paternally expressed non-coding Air RNA. Expression of Air is correlated with repression of all three genes on the paternal allele; however, Air RNA overlaps just one of these genes in an antisense orientation. Here we show, by inserting a polyadenylation signal that truncates 96% of the RNA transcript, that Air RNA is required for silencing. The truncated Air allele maintains imprinted expression and methylation of the Air promoter, but shows complete loss of silencing of the Igf2r/Slc22a2/Slc22a3 gene cluster on the paternal chromosome. Our results indicate that non-coding RNAs have an active role in genomic imprinting.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging (Albany NY)
                Aging
                Aging (Albany NY)
                Impact Journals
                1945-4589
                31 March 2020
                25 March 2020
                : 12
                : 6
                : 4711-4726
                Affiliations
                [1 ]Department of Thoracic Surgery, Peking Union Medical College Hospital, Wangfujing, Dongcheng, Beijing 100730, P.R. China
                [2 ]Beijing 100biotech Co., Ltd., Beijing 100006, China
                Author notes
                [*]

                Equal contribution

                Correspondence to: Yushang Cui; email: cuiyushang@126.com
                Article
                102673 102673
                10.18632/aging.102673
                7138551
                32209729
                14a4c884-d77c-4441-8590-1c89f235278c
                Copyright © 2020 Xu et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 September 2019
                : 25 December 2019
                Categories
                Research Paper

                Cell biology
                lncrna,xist,apoptosis,pyroptosis,chemoresistance,nsclc
                Cell biology
                lncrna, xist, apoptosis, pyroptosis, chemoresistance, nsclc

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