Abstract
BackgroundIntratumour heterogeneous gene expression among cancer and cancer stem cells (CSCs) can cause failure of current targeted therapies because each drug aims to target the function of a single gene. Long mononucleotide A-T repeats are cis-regulatory transcriptional elements that control many genes, increasing the expression of numerous genes in various cancers, including lung cancer. Therefore, targeting A-T repeats may dysregulate many genes driving cancer development. Here, we tested a peptide nucleic acid (PNA) oligo containing a long A-repeat sequence [A(15)] to disrupt the transcriptional control of the A-T repeat in lung cancer and CSCs.MethodsFirst, we separated CSCs from parental lung cancer cell lines. Then, we evaluated the role of A-T repeat gene regulation by counting the number of repeats in differentially regulated genes between CSCs and the parental cells of the CSCs. After testing the dosage and effect of PNA-A15 on normal and cancer cell toxicity and CSC phenotypes, we analysed genome-wide expression to identify dysregulated genes in CSCs.ResultsThe number of A-T repeats in genes differentially regulated between CSCs and parental cells differed. PNA-A15 was toxic to lung cancer cells and CSCs but not to noncancer cells. Finally, PNA-A15 dysregulated a number of genes in lung CSCs.ConclusionPNA-A15 is a promising novel targeted therapy agent that targets the transcriptional control activity of multiple genes in lung CSCs.
Highlights
Intratumour heterogeneous gene expression among cancer and cancer stem cells (CSCs) can cause failure of current targeted therapies because each drug aims to target the function of a single gene
We found that the expression levels of CSC markers Cluster of differentiation 133 (CD133), Cluster of differentiation 44 (CD44), ATP-binding cassette super-family G member 2 (ABCG2) and Aldehyde dehydrogenalse 1 (ALDH1A1) were all dramatically increased in the enriched CSC population compared to their parental cells (Fig. 1a)
The data represent 69 overlapping genes filtered with a P value ≤ 0.01, and we found that peptide nucleic acid (PNA)-A15 dysregulated the A and T repeat densities of downregulated genes that are related to genes acting as proto-oncogenes and inducing tumorigenesis in both cell lines
Summary
Intratumour heterogeneous gene expression among cancer and cancer stem cells (CSCs) can cause failure of current targeted therapies because each drug aims to target the function of a single gene. Long mononu‐ cleotide A-T repeats are cis-regulatory transcriptional elements that control many genes, increasing the expression of numerous genes in various cancers, including lung cancer. We tested a peptide nucleic acid (PNA) oligo containing a long A-repeat sequence [A(15)] to disrupt the transcriptional control of the A-T repeat in lung cancer and CSCs. Cancer stem cells (CSCs) are the major reason for the devastating effects of cancer [1]. Intratumour heterogeneous gene expression among cancer and CSCs can cause a failure of current targeted therapy because each drug aims to target the function of a single gene [3].
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