Oncotarget

Priority Research Papers:

Loss of p53-inducible long non-coding RNA LINC01021 increases chemosensitivity

Markus Kaller, Ursula Götz and Heiko Hermeking _

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Oncotarget. 2017; 8:102783-102800. https://doi.org/10.18632/oncotarget.22245

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Abstract

Markus Kaller1, Ursula Götz1 and Heiko Hermeking1,2,3

1Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany

2German Cancer Consortium (DKTK), Heidelberg, Germany

3German Cancer Research Center (DKFZ), Heidelberg, Germany

Correspondence to:

Heiko Hermeking, email: heiko.hermeking@med.uni-muenchen.de

Keywords: p53; LINC01021; chemosensitivity; colorectal cancer; tumor suppression

Received: September 29, 2017    Accepted: October 02, 2017    Published: November 01, 2017

ABSTRACT

We have previously identified the long non-coding RNA LINC01021 as a direct p53 target (Hünten et al. Mol Cell Proteomics. 2015; 14:2609-2629). Here, we show that LINC01021 is up-regulated in colorectal cancer (CRC) cell lines upon various p53-activating treatments. The LINC01021 promoter and the p53 binding site lie within a MER61C LTR, which originated from insertion of endogenous retrovirus 1 (ERV1) sequences. Deletion of this MER61C element by a CRISPR/Cas9 approach, as well as siRNA-mediated knockdown of LINC01021 RNA significantly enhanced the sensitivity of the CRC cell line HCT116 towards the chemotherapeutic drugs doxorubicin and 5-FU, suggesting that LINC01021 is an integral part of the p53-mediated response to DNA damage. Inactivation of LINC01021 and also its ectopic expression did not affect p53 protein expression and transcriptional activity, implying that LINC01021 does not feedback to p53. Furthermore, in CRC patient samples LINC01021 expression positively correlated with a wild-type p53-associated gene expression signature. LINC01021 expression was increased in primary colorectal tumors and displayed a bimodal distribution that was particularly pronounced in the mesenchymal CMS4 consensus molecular subtype of CRCs. CMS4 tumors with low LINC01021 expression were associated with poor patient survival. Our results suggest that the genomic redistribution of ERV1-derived p53 response elements and generation of novel p53-inducible lncRNA-encoding genes was selected for during primate evolution as integral part of the cellular response to various forms of genotoxic stress.


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