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P53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino.

ABSTRACT: Many long noncoding RNA (lncRNA) genes exist near cancer-associated loci, yet evidence connecting lncRNA functions to recurrent genetic alterations in cancer are lacking. Here, we report that DINO, the lncRNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formation independent of p21, the protein encoded at the locus. Loss of one or two alleles of Dino impairs p53 signaling and apoptosis, resulting in a haplo-insufficient tumor suppressor phenotype in genetically defined mouse models of tumorigenesis. A discrete region of the DINO/CDKN1A locus is recurrently hypermethylated in human cancers, silencing DINO but not CDKN1A, the gene encoding p21. Hypermethylation silences DINO, impairs p53 signaling pathway in trans, and is mutually exclusive with TP53 alterations, indicating that DINO and TP53 comprise a common tumor suppressor module. Therefore, DINO encodes a lncRNA essential for tumor suppression that is recurrently silenced in human cancers as a mechanism to escape p53-dependent tumor suppression.

SUBMITTER: Marney CB

PROVIDER: S-EPMC8287872 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino.

Marney Christina B CB Anderson Erik S ES Adnan Mutayyaba M Peng Kai-Lin KL Hu Ya Y Weinhold Nils N Schmitt Adam M AM

Cell reports 20210601 13

Many long noncoding RNA (lncRNA) genes exist near cancer-associated loci, yet evidence connecting lncRNA functions to recurrent genetic alterations in cancer are lacking. Here, we report that DINO, the lncRNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formation independent of p21, the protein encoded at the locus. Loss of one or two alleles of Dino impairs p53 signaling and apoptosis, resulting in a haplo-insufficient tumor suppressor phenotype in genetically defi ...[more]

PMID: 34192538

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Project description:BackgroundThe damage-induced non-coding (DINO) RNA is a newly identified long non-coding RNA (lncRNA) found in human cells with DNA damage. The treatment of tumors with cisplatin can induce DNA damage; however, whether the lncRNA DINO is involved in the treatment of non-small cell lung cancer (NSCLC) has not yet been elucidated.MethodsThe expression of the lncRNA DINO in lung adenocarcinoma cells was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The lung adenocarcinoma cell line, A549, and derived cisplatin-resistant cell line, A549R, were selected to construct cell models with lncRNA DINO overexpression or interference via lentiviral transfection. After cisplatin treatment, changes in the apoptosis rate were measured. Changes in the p53-Bax axis were detected by qRT-PCR and Western blot. Cycloheximide (CHX) interference demonstrated the stability of p53 with new protein production induced by the lncRNA DINO. The in vivo experiments involved intraperitoneal injection of nude mice with cisplatin after subcutaneous tumor formation, and the tumor diameters and weights were recorded. Immunohistochemistry and hematoxylin and eosin (H&E) staining were performed following tumor removal.ResultsWe found that the lncRNA DINO was significantly down-regulated in NSCLC. DINO overexpression enhanced the sensitivity of NSCLC cells to cisplatin, while DINO down-regulation decreased the sensitivity of NSCLC cells to cisplatin. Mechanistic investigation indicated that DINO enhanced the stability of p53 and mediated the activation of the p53-Bax signaling axis. Our results also demonstrated that the lncRNA DINO could partially reverse cisplatin resistance induced by silencing the p53-Bax axis, and could inhibit subcutaneous tumorigenesis in nude mice after cisplatin treatment in vivo.ConclusionsThe lncRNA DINO regulates the sensitivity of lung adenocarcinoma to cisplatin by stabilizing p53 and activating the p53-Bax axis, and thus, may be a novel therapeutic target to overcome cisplatin resistance.

Dataset Information

P53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino.

Publications

p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino.

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