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 language | English |
---|---|
Pages (from-to) | 1499-1511 |
Number of pages | 13 |
Journal | RNA Biology |
Volume | 15 |
Issue number | 12 |
DOIs | |
State | Published - 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.
Funders | Funder number |
---|---|
Biomaterial Bank Heidelberg | |
DKFZ-ZMBH Alliance | |
FACS Core Facility | |
Lung Biobank Heidelberg | |
ZMBH Mass Spectrometry Core Facility | |
Deutsche Forschungsgemeinschaft | DFG Di 1421/7-1 |
Deutsche Zentrum für Lungenforschung |
Keywords
- LINC00673
- long noncoding RNA
- lung cancer
- p53
- senescence