Targeting LINC00673 expression triggers cellular senescence in lung cancer

Anna Roth, Karine Boulay, Matthias Groß, Maria Polycarpou-Schwarz, Frédérick A. Mallette, Marine Regnier, Or Bida, Doron Ginsberg, Arne Warth, Philipp A. Schnabel, Thomas Muley, Michael Meister, Heike Zabeck, Hans Hoffmann, Sven Diederichs

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Aberrant expression of noncoding RNAs plays a critical role during tumorigenesis. To uncover novel functions of long non-coding RNA (lncRNA) in lung adenocarcinoma, we used a microarray-based screen identifying LINC00673 with elevated expression in matched tumor versus normal tissue. We report that loss of LINC00673 is sufficient to trigger cellular senescence, a tumor suppressive mechanism associated with permanent cell cycle arrest, both in lung cancer and normal cells in a p53-dependent manner. LINC00673-depleted cells fail to efficiently transit from G1- to S-phase. Using a quantitative proteomics approach, we confirm the modulation of senescence-associated genes as a result of LINC00673 knockdown. In addition, we uncover that depletion of p53 in normal and tumor cells is sufficient to overcome LINC00673-mediated cell cycle arrest and cellular senescence. Furthermore, we report that overexpression of LINC00673 reduces p53 translation and contributes to the bypass of Ras-induced senescence. In summary, our findings highlight LINC00673 as a crucial regulator of proliferation and cellular senescence in lung cancer.

Original languageEnglish
Pages (from-to)1499-1511
Number of pages13
JournalRNA Biology
Volume15
Issue number12
DOIs
StatePublished - 2 Dec 2018

Bibliographical note

Publisher Copyright:
© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

Funding

Research in the Diederichs lab is supported by the Deutsche Forschungsgemeinschaft (DFG Di 1421/7-1) and the RNA@DKFZ Cross Program Topic. The patient tissues were provided by the Lung Biobank Heidelberg, member of the Biomaterial Bank Heidelberg (BMBH), and the biobank platform of the German Center for Lung Research (DZL). We would like to thank Vladimir Benes and Tomi Ivacevic (EMBL, Heidelberg, Germany) for providing the infrastructure and support with the microarray analysis; Johanna Schott (DKFZ-ZMBH Alliance, Heidelberg, Germany) for the re-annotation of the microarray; Stefanie Grund for the cellular fractionation; Hans Johansson (LGC Biosearch Technologies) for the design of the FISH probes; the DKFZ Light Microscopy Core Facility, the ZMBH Flow Cytometry & FACS Core Facility (Heidelberg, Germany) for the technical support, the ZMBH Mass Spectrometry Core Facility for the sample preparation, technical support and data analysis. This work is part of the PhD thesis of A.R. Research in the Diederichs lab is supported by the Deutsche Forschungsgemeinschaft (DFG Di 1421/7-1) and the RNA@DKFZ Cross Program Topic.

FundersFunder number
Biomaterial Bank Heidelberg
DKFZ-ZMBH Alliance
FACS Core Facility
Lung Biobank Heidelberg
ZMBH Mass Spectrometry Core Facility
Deutsche ForschungsgemeinschaftDFG Di 1421/7-1
Deutsche Zentrum für Lungenforschung

    Keywords

    • LINC00673
    • long noncoding RNA
    • lung cancer
    • p53
    • senescence

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