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

Markus Kaller,Ursula Götz,Heiko Hermeking

doi:10.18632/oncotarget.22245

Markus Kaller, Ursula Götz + Show 1 more

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https://doi.org/10.18632/oncotarget.22245

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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.

Highlights

The p53 transcription factor is encoded by a tumor suppressor gene, which represents the most commonly mutated gene in human cancer [1]
LINC01021 is a direct p53 target regulated by an endogenous retrovirus 1 (ERV1)-derived Long terminal repeat (LTR) and its expression is highly dependent on p53 in colorectal cancer (CRC) cell lines
We show that LINC01021 is consistently up-regulated in a p53-dependent manner in CRC cell lines upon treatment with p53activating agents used for chemotherapy of CRC and other types of tumors

Summary

Introduction

The p53 transcription factor is encoded by a tumor suppressor gene, which represents the most commonly mutated gene in human cancer [1]. Many of the cancers without p53 mutation harbor alterations up- or down-stream of p53, which impede the ability of p53 to suppress tumors. Most p53 mutations target the DNA binding properties of p53, suggesting that the regulation of specific target genes is central for the tumor suppression mediated by p53. P53 directly activates a large set of genes, which mediate numerous cellular functions involved in tumor suppression, such as cell cycle arrest, apoptosis, senescence, and DNA repair [3]. Apart from protein-coding genes, non-coding RNAs are transcriptional targets of p53. Long non-coding RNAs (lncRNAs) have emerged as downstream effectors of tumor suppression by p53 (reviewed in [5, 6])

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