Final Report Summary - CANCERLINC (Functional and Mecahnistic Roles of Large Intergenic Non-coding RNAs in Cancer)
Mammalian cells encode thousands of RNA molecules structurally similar to protein coding genes -they are large, spliced, poly-adenylated, transcribed by RNA Pol II, with conserved promoters and exonic structures -however lack coding capacity. Although thousands exist, only few of these large intergenic non-coding RNAs (lincRNAs) have been characterized. The few that have show powerful biological roles as regulators of gene expression by diverse epigenetic and non-epigenetic mechanisms. Significantly, their expression patterns suggest that some lincRNAs are involved in cellular pathways critical in cancer, like the p53 pathway.
Supporting this idea, we found that the transcription factor p53, which is crucial for the maintenance of cellular homeostasis, specifically regulates the expression of dozens of lncRNAs in human cells, which constitute active components of this important tumor suppressor pathway. Among them, we have shown that LINC-PINT acts as an inhibitor of tumor invasion through its interaction with the Polycomb Repressive Complex 2. The activity of this lincRNA is dependent of a hihghly conserved sequence element, which indicates an important connection between the RNA sequence and function.
While p53 is able to specifically activate the expression of lincRNAs involved in tumor suppression, other lncRNAs can promote the malignant phenotype of cancer cells, acting as oncogenes. We found that in p53-deficient cells, a different set of lncRNAs is induced. These include a so far uncharacterized lncRNA that we named CONCR (cohesion regulator noncoding RNA), transcriptionally activated by MYC, which is upregulated in multiple cancer types. The expression of CONCR is cell cycle-regulated, and it is required for cell cycle progression and DNA replication. Moreover, cells depleted of CONCR show severe defects in sister chromatid cohesion, suggesting an essential role for CONCR in cohesion establishment during cell division. CONCR interacts with and regulates the activity of DDX11, a DNA-dependent ATPase and helicase involved in DNA replication. These findings suggest a novel mechanism of action for CONCR in the modulation of DDX11 enzymatic activity, unveiling the direct involvement of a lncRNA in the establishment of sister chromatid cohesion.
Altogether, we have shown that lncRNAs are specifically regulated in cancer cells by different oncogenic or tumor suppressor stimuli, and contribute to their downstream function by diverse molecular mechanisms. These findings open up our view of these cancer-relevant processes and point out to lncRNAs as possible targets for therapies.
Supporting this idea, we found that the transcription factor p53, which is crucial for the maintenance of cellular homeostasis, specifically regulates the expression of dozens of lncRNAs in human cells, which constitute active components of this important tumor suppressor pathway. Among them, we have shown that LINC-PINT acts as an inhibitor of tumor invasion through its interaction with the Polycomb Repressive Complex 2. The activity of this lincRNA is dependent of a hihghly conserved sequence element, which indicates an important connection between the RNA sequence and function.
While p53 is able to specifically activate the expression of lincRNAs involved in tumor suppression, other lncRNAs can promote the malignant phenotype of cancer cells, acting as oncogenes. We found that in p53-deficient cells, a different set of lncRNAs is induced. These include a so far uncharacterized lncRNA that we named CONCR (cohesion regulator noncoding RNA), transcriptionally activated by MYC, which is upregulated in multiple cancer types. The expression of CONCR is cell cycle-regulated, and it is required for cell cycle progression and DNA replication. Moreover, cells depleted of CONCR show severe defects in sister chromatid cohesion, suggesting an essential role for CONCR in cohesion establishment during cell division. CONCR interacts with and regulates the activity of DDX11, a DNA-dependent ATPase and helicase involved in DNA replication. These findings suggest a novel mechanism of action for CONCR in the modulation of DDX11 enzymatic activity, unveiling the direct involvement of a lncRNA in the establishment of sister chromatid cohesion.
Altogether, we have shown that lncRNAs are specifically regulated in cancer cells by different oncogenic or tumor suppressor stimuli, and contribute to their downstream function by diverse molecular mechanisms. These findings open up our view of these cancer-relevant processes and point out to lncRNAs as possible targets for therapies.