Function of the p53-induced lncRNA LINC01021 in suppression of colorectal cancer
Final Report Abstract
The TP53 tumor-suppressor gene represents the most commonly mutated gene in human cancer. It encodes the p53 transcription factor, which is activated by various forms of cellular stress, such as DNA damage induced by irradiation or aberrant oncogene activation. P53 regulates a large set of genes, which regulate numerous cellular functions that mediate tumor suppression by p53, such as cell cycle arrest, apoptosis, senescence, and DNA repair. Apart from the many protein-coding genes that have been functionally characterized as direct p53 targets, genes encoding noncoding RNAs are also directly regulated by p53. Growing evidence indicates that p53-induced long noncoding (lnc) RNAs constitute an elaborate regulatory network that mediates and/or modulates p53 function and, thus, tumor suppression. The p53- induced LINC01021 lncRNA has been suggested to represent a negative feedback regulator of p53 protein stability under non-stress conditions. Furthermore, the loss of LINC01021 in p53-proficient colorectal cancer (CRC) cell lines results in increased sensitivity to DNA-damaging chemotherapeutics. In order to analyze whether LINC01021 affects the transcriptional program of p53 independently from the direct feedback regulation of p53, we studied the effect of CRISPR/Cas9-mediated abrogation of p53-induced LINC01021 transcription on genomewide RNA expression changes after the activation of ectopic p53 in CRC cells by RNA-Seq analyses. Our results demonstrate diverse regulatory effects of LINC01021 on a subset of p53-regulated genes either via attenuated expression or altered transcript isoform usage. Taken together, our study provides a comprehensive framework and resource for further analyses of LINC01021 function downstream of p53.
Publications
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LINC01021 Attenuates Expression and Affects Alternative Splicing of a Subset of p53-Regulated Genes. Cancers, 16(9), 1639.
Kaller, Markus; Forné, Ignasi; Imhof, Axel & Hermeking, Heiko
